US9726677B2 - Proteomic IPF markers - Google Patents

Proteomic IPF markers Download PDF

Info

Publication number
US9726677B2
US9726677B2 US14/213,970 US201414213970A US9726677B2 US 9726677 B2 US9726677 B2 US 9726677B2 US 201414213970 A US201414213970 A US 201414213970A US 9726677 B2 US9726677 B2 US 9726677B2
Authority
US
United States
Prior art keywords
pulmonary disease
fibrotic pulmonary
expression level
disease marker
fibrotic
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active - Reinstated
Application number
US14/213,970
Other languages
English (en)
Other versions
US20140286929A1 (en
Inventor
Karl Kossen
Xiaoli Qin
Sharlene R. Lim
Scott S. Seiwert
Donald Ruhrmund
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genentech Inc
Original Assignee
Intermune Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Intermune Inc filed Critical Intermune Inc
Priority to US14/213,970 priority Critical patent/US9726677B2/en
Assigned to INTERMUNE, INC. reassignment INTERMUNE, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SEIWERT, SCOTT S., KOSSEN, KARL, LIM, SHARLENE R., QIN, XIAOLI, RUHRMUND, DONALD
Publication of US20140286929A1 publication Critical patent/US20140286929A1/en
Application granted granted Critical
Publication of US9726677B2 publication Critical patent/US9726677B2/en
Assigned to INTERMUNE, INC. reassignment INTERMUNE, INC. CHANGE OF ASSIGNEE ADDRESS Assignors: INTERMUNE, INC.
Assigned to GENENTECH, INC. reassignment GENENTECH, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: INTERMUNE, INC.
Active - Reinstated legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/118—Prognosis of disease development
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases

Definitions

  • IIPs interstitial pneumonias
  • IPF interstitial lung disease idiopathic pulmonary fibrosis
  • ATS/ERS Am J Respir Crit Care Med 2002: 165(2): 277-304.
  • Patients diagnosed with IPF typically experience progressive pulmonary insufficiency, and most die of respiratory failure.
  • the ratio of the estimated prevalence (90,000 individuals) and incidence (30,000 individuals) of IPF in the United States reflects this poor prognosis (Raghu G, Weycker D, Edelsberg J, Bradford W Z, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2006: 174(7): 810-816).
  • the clinical course of IPF is highly variable and may be characterized by periods of relative stability, chronic decline, or periods of rapid decline (known as acute exacerbations).
  • Clinical and physiological parameters e.g., forced vital capacity, diffusing capacity of carbon monoxide DLco, six minute walk test distance
  • IPF intravascular pressure
  • risk prediction models that incorporate these components (or change therein) are relatively successful in staging patients and predicting risk of mortality.
  • management approaches that are based on molecular information (such as that derived from protein markers) may enable better monitoring of disease progression and risk of progression in patients with IPF.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a subject that has or is at risk for developing a fibrotic pulmonary disease includes (i) obtaining a biological sample from said subject and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in the biological sample.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 1A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to the standard control indicates that the subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on the expression level in step (ii), determining whether the subject has or is at risk for developing a fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a fibrotic pulmonary disease patient (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 1A or Table 1B relative to the standard control indicates that the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, wherein when the second expression level of a protein set forth in Table 1A is greater than the first level of a protein set forth in Table 1A; or wherein when the second expression level of a protein set forth in Table 1B is smaller than the first level of a protein set forth in Table 1B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining the fibrotic pulmonary disease activity in the patient.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, thereby determining the fibrotic pulmonary disease activity in the patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, thereby determining the a change in fibrotic pulmonary disease activity in the patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a change in fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining the change in fibrotic pulmonary disease activity in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, thereby determining the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby monitoring the effect of treatment for a fibrotic pulmonary disease in the patient; and (iii) based at least in part on the expression level in step (ii), monitoring the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes administering to the subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 1A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 1B relative to a standard control, and (ii) when an elevated expression level of the fibrotic pulmonary disease marker protein of Table 1A or a decreased expression level of the fibrotic pulmonary disease marker protein of Table 1B is found relative to the standard control, administering to the subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 1A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 1B, thereby treating the subject.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in a subject that has or is at risk for developing a fibrotic pulmonary disease includes (i) obtaining a biological sample from the subject, and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in the biological sample.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject, (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 3A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to the standard control indicates that the subject has or is at risk of developing a fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the subject has or is at risk for developing a fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 3A or 3B in a fibrotic pulmonary disease patient, (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 3A or 3B relative to the standard control indicates that the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point, (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point, (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, wherein when the second expression level of a protein set forth in Table 3A is greater than the first level of a protein set forth in Table 3A, or wherein when the second expression level of a protein set forth in Table 3B is smaller than the first level of a protein set forth in Table 3B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes, (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining said fibrotic pulmonary disease activity in the patient.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point, (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point, (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, thereby determining the fibrotic pulmonary disease activity in the patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, thereby determining a change in fibrotic pulmonary disease activity in a patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a change in fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining the change in fibrotic pulmonary disease activity in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, thereby monitoring the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby monitoring the effect of treatment for a fibrotic pulmonary disease in the patient; and (iii) based at least in part on the expression level in step (ii), monitoring the effect of treatment for a fibrotic pulmonary disease in the patient
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes administering to the subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B, thereby treating a fibrotic pulmonary disease in the subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 3A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 3B relative to a standard control, and (ii) when an elevated expression level of the fibrotic pulmonary disease marker protein of Table 3A or a decreased expression level of the fibrotic pulmonary disease marker protein of Table 3B is found relative to the standard control, administering to the subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 3A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 3B, thereby treating the subject.
  • a kit in one aspect, includes a marker protein binding agent capable of binding to a substance within a biological sample from a human subject having or at risk of developing a fibrotic pulmonary disease, wherein the substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B); and a detecting reagent or a detecting apparatus capable of indicating binding of the marker protein binding agent to the substance.
  • a marker protein binding agent capable of binding to a substance within a biological sample from a human subject having or at risk of developing a fibrotic pulmonary disease, wherein the substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B); and a detecting reagent or a detecting apparatus capable of indicating binding of the marker protein
  • a kit in one aspect, includes a marker protein binding agent capable of binding to a substance within a biological sample from a human subject having a fibrotic pulmonary disease, wherein the substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B); and a detecting reagent or a detecting apparatus capable of indicating binding of the marker protein binding agent to the substance.
  • a complex in vitro includes a marker protein binding agent bound to a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B), wherein the fibrotic pulmonary disease marker protein is extracted from a human subject having or at risk of developing a fibrotic pulmonary disease.
  • a complex in vitro includes a marker protein binding agent bound to a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B), wherein the fibrotic pulmonary disease marker protein is extracted from a human subject having a fibrotic pulmonary disease.
  • FIG. 1 Overview of the proteomics assay.
  • P The specific protein to be measured (P,) binds tightly to its cognate SOMAmer binding molecule (S), which includes a photo-cleavable biotin (PCB) and fluorescent label (L) at the 5′ end.
  • S SOMAmer binding molecule
  • PCB photo-cleavable biotin
  • L fluorescent label
  • Step 2 Bound protein-SOMAmer complexes are captured onto streptavidin coated beads (SA) by photo-cleavable biotin on the SOMAmer. Unbound proteins are washed away. Bound proteins are tagged with biotin (B).
  • SA streptavidin coated beads
  • B Bound proteins are tagged with biotin
  • B Biotin
  • Step 3 The photo-cleavable biotin is cleaved by UV light (hn) and the protein-SOMAmer complexes are released into solution.
  • Step 4 The protein-SOMAmer complexes are captured onto SA and the SOMAmers are eluted into solution (Step 5) and recovered for quantification in Step 6, hybridization to a custom DNA microarray.
  • Each probe spot contains DNA with sequence complementary to a specific SOMAmer, and the fluorescent intensity of each probe spot is proportional to the amount of SOMAmer recovered, which is proportional to the amount of protein present in the original sample.
  • PCB Photo-cleavable biotin
  • SOMAmer Slow off-rate modified aptamer.
  • FIG. 2 Comparison of relative rank of pathways defined by differentially expressed proteins to those defined by the proteins on the panel as a whole.
  • FIG. 3 Hierarchical Clustering of IPF patients.
  • FIG. 4 Hierarchical Clustering of IPF patients.
  • FIG. 5 - FIG. 47 Fibrotic pulmonary disease biomarker proteins that predict disease progression in patient cohort #1 using aptamer based proteomic platform for determination of protein levels. The following description applies to the histograms shown in FIG. 5 - FIG. 47 :
  • Kaplan-Meier curve for All-Cause Mortality (Lower left histogram) Kaplan-Meier curve for All-Cause Mortality. X-axis indicates days, y-axis indicates percent survival. Subjects are grouped based on a protein level cut-off suggested by CART analysis. Number of subjects above and below cut-off are indicated (i.e. “high N” and “low N”). Unadjusted p-value for significance is shown.
  • FIG. 48 - FIG. 57 Selected fibrotic pulmonary disease biomarker proteins that predict disease progression in two independent patient cohorts. Plasma protein level was quantitated by ELISA. The following description applies to the plots shown in FIG. 48 - FIG. 57 :
  • disease refers to any deviation from the normal health of a mammal and includes a state when disease symptoms are present, as well as conditions in which a deviation (e.g., infection, gene mutation, genetic defect, etc.) has occurred, but symptoms are not yet manifested.
  • the methods disclosed herein are suitable for use in a patient that is a member of the Vertebrate class, Mammalia, including, without limitation, primates, livestock and domestic pets (e.g., a companion animal).
  • a patient will be a human patient.
  • pulmonary disease pulmonary disorder
  • lung disease etc.
  • the term is used to broadly refer to lung disorders characterized by difficulty breathing, coughing, airway discomfort and inflammation, increased mucus, and/or pulmonary fibrosis.
  • An “airway mucosal sample” can be obtained using methods known in the art, e.g., a bronchial epithelial brush as described herein. Additional methods include endobronchial biopsy, bronchial wash, bronchoalveolar lavage, whole lung lavage, transendoscopic biopsy, and transtracheal wash.
  • subject as used herein includes all members of the animal kingdom prone to suffering from the indicated disorder. In some aspects, the subject is a mammal, and in some aspects, the subject is a human.
  • a “control” sample or value refers to a sample that serves as a reference, usually a known reference, for comparison to a test sample.
  • a test sample can be taken from a patient suspected of having a given pulmonary disease and compared to samples from a known pulmonary disease patient, or a known normal (non-disease) individual.
  • a control can also represent an average value gathered from a population of similar individuals, e.g., pulmonary disease patients or healthy individuals with a similar medical background, same age, weight, etc.
  • a control value can also be obtained from the same individual, e.g., from an earlier-obtained sample, prior to disease, or prior to treatment.
  • controls can be designed for assessment of any number of parameters.
  • Controls are valuable in a given situation and be able to analyze data based on comparisons to control values. Controls are also valuable for determining the significance of data. For example, if values for a given parameter are widely variant in controls, variation in test samples will not be considered as significant.
  • a pharmaceutical composition will generally comprise agents for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.
  • a dose refers to the amount of active ingredient given to an individual at each administration.
  • the dose will generally refer to the amount of pulmonary disease treatment, anti-inflammatory agent, agonist or antagonist.
  • the dose will vary depending on a number of factors, including the range of normal doses for a given therapy, frequency of administration; size and tolerance of the individual; severity of the condition; risk of side effects; and the route of administration.
  • dose form refers to the particular format of the pharmaceutical, and depends on the route of administration.
  • a dosage form can be in a liquid form for nebulization, e.g., for inhalants, in a tablet or liquid, e.g., for oral delivery, or a saline solution, e.g., for injection.
  • Treatment can refer to any delay in onset, reduction in the frequency or severity of symptoms, amelioration of symptoms, improvement in patient comfort and/or respiratory function, etc.
  • the effect of treatment can be compared to an individual or pool of individuals not receiving a given treatment, or to the same patient prior to, or after cessation of, treatment.
  • Treating” or “treatment” as used herein also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • treatment as used herein includes any cure, amelioration, or prevention of a disease.
  • Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms (e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
  • the disease's symptoms e.g., ocular pain, seeing halos around lights, red eye, very high intraocular pressure
  • fully or partially remove the disease's underlying cause shorten a disease's duration, or do a combination of these things.
  • Treating” and “treatment” as used herein include prophylactic treatment.
  • Treatment methods include administering to a subject a therapeutically effective amount of an active agent.
  • the administering step may consist of a single administration or may include a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof.
  • the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • prevent refers to a decrease in the occurrence of pulmonary disease symptoms in a patient. As indicated above, the prevention may be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would likely occur absent treatment.
  • a therapeutically effective amount refers to that amount of the therapeutic agent sufficient to ameliorate the disorder, as described above.
  • a therapeutically effective amount will show an increase or decrease of at least 5%, 10%, 15%, 20%, 25%, 40%, 50%, 60%, 75%, 80%, 90%, or at least 100%.
  • Therapeutic efficacy can also be expressed as “-fold” increase or decrease.
  • a therapeutically effective amount can have at least a 1.2-fold, 1.5-fold, 2-fold, 5-fold, or more effect over a control.
  • prognosis refers to a relative probability that a pulmonary disease is present in the subject.
  • prognosis refers to a relative probability that a certain future outcome may occur in the subject.
  • prognosis can refer to the likelihood that an individual will develop a pulmonary disease, or the likely severity of the disease (e.g., severity of symptoms, rate of functional decline, survival, etc.). The terms are not intended to be absolute, as will be appreciated by any one of skill in the field of medical diagnostics.
  • correlating in reference to determination of a pulmonary disease risk factor, refers to comparing the presence or amount of the risk factor (e.g., decreased or increased expression of an IPF biomarker protein) in an individual to its presence or amount in persons known to suffer from, or known to be at risk of, the pulmonary disease, or in persons known to be free of pulmonary disease, and assigning an increased or decreased probability of having/developing the pulmonary disease to an individual based on the assay result(s).
  • the risk factor e.g., decreased or increased expression of an IPF biomarker protein
  • Nucleic acid or “oligonucleotide” or “polynucleotide” or grammatical equivalents used herein means at least two nucleotides covalently linked together. Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50 or more nucleotides in length, up to about 100 nucleotides in length. Nucleic acids and polynucleotides are a polymers of any length, including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000, 7000, 10,000, etc.
  • a nucleic acid of the present invention will generally contain phosphodiester bonds, although in some cases, nucleic acid analogs are included that may have alternate backbones, comprising, e.g., phosphoramidate, phosphorothioate, phosphorodithioate, or O-methylphophoroamidite linkages (see Eckstein, Oligonucleotides and Analogues: A Practical Approach, Oxford University Press); and peptide nucleic acid backbones and linkages.
  • Other analog nucleic acids include those with positive backbones; non-ionic backbones, and non-ribose backbones, including those described in U.S. Pat. Nos.
  • nucleic acids containing one or more carbocyclic sugars are also included within one definition of nucleic acids. Modifications of the ribose-phosphate backbone may be done for a variety of reasons, e.g., to increase the stability and half-life of such molecules in physiological environments or as probes on a biochip. Mixtures of naturally occurring nucleic acids and analogs can be made; alternatively, mixtures of different nucleic acid analogs, and mixtures of naturally occurring nucleic acids and analogs may be made.
  • nucleic acids e.g., genomic sequences or subsequences or coding sequences
  • polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues or nucleotides that are the same (i.e., 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more identity over a specified region), when compared and aligned for maximum correspondence over a comparison window, or designated region as measured using one of the following sequence comparison algorithms or by manual alignment and visual inspection.
  • sequences are then said to be “substantially identical.” This definition also refers to the compliment of a test sequence. Optionally, the identity exists over a region that is at least about 10 to about 100, about 20 to about 75, about 30 to about 50 amino acids or nucleotides in length.
  • BLAST and BLAST 2.0 algorithms are described in Altschul et al., Nuc. Acids Res. 25:3389-3402 (1977) and Altschul et al., J. Mol. Biol. 215:403-410 (1990), respectively.
  • the software for performing BLAST analyses is publicly available through the website of the National Center for Biotechnology Information (ncbi.nlm.nih.gov).
  • polypeptide “peptide” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers, those containing modified residues, and non-naturally occurring amino acid polymer.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function similarly to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, y-carboxyglutamate, and 0-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, e.g., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogs may have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions similarly to a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • Constantly modified variants applies to both amino acid and nucleic acid sequences. With respect to particular nucleic acid sequences, conservatively modified variants refers to those nucleic acids which encode identical or essentially identical amino acid sequences, or where the nucleic acid does not encode an amino acid sequence, to essentially identical or associated, e.g., naturally contiguous, sequences. Because of the degeneracy of the genetic code, a large number of functionally identical nucleic acids encode most proteins. For instance, the codons GCA, GCC, GCG and GCU all encode the amino acid alanine.
  • nucleic acid variations are “silent variations,” which are one species of conservatively modified variations.
  • Every nucleic acid sequence herein which encodes a polypeptide also describes silent variations of the nucleic acid.
  • each codon in a nucleic acid except AUG, which is ordinarily the only codon for methionine, and TGG, which is ordinarily the only codon for tryptophan
  • TGG which is ordinarily the only codon for tryptophan
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters, adds or deletes a single amino acid or a small percentage of amino acids in the encoded sequence is a “conservatively modified variant” where the alteration results in the substitution of an amino acid with a chemically similar amino acid. Conservative substitution tables providing functionally similar amino acids are well known in the art. Such conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles of the invention.
  • a “label” or a “detectable moiety” is a composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, or other physical means.
  • useful labels include 32 P, fluorescent dyes, electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin, digoxigenin, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. Any method known in the art for conjugating an antibody to the label may be employed, e.g., using methods described in Hermanson, Bioconjugate Techniques 1996, Academic Press, Inc., San Diego.
  • a “labeled protein or polypeptide” is one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic, van der Waals, electrostatic, or hydrogen bonds to a label such that the presence of the labeled protein or polypeptide may be detected by detecting the presence of the label bound to the labeled protein or polypeptide.
  • methods using high affinity interactions may achieve the same results where one of a pair of binding partners binds to the other, e.g., biotin, streptavidin.
  • Antibody refers to a polypeptide comprising a framework region from an immunoglobulin gene or fragments thereof that specifically binds and recognizes an antigen, e.g., a specific bacterial antigen.
  • the “variable region” contains the antigen-binding region of the antibody (or its functional equivalent) and is most critical in specificity and affinity of binding. See Paul, Fundamental Immunology (2003).
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer.
  • Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one “light” (about 25 kD) and one “heavy” chain (about 50-70 kD).
  • the N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms variable light chain (V L ) and variable heavy chain (V H ) refer to these light and heavy chains respectively.
  • Antibodies can exist as intact immunoglobulins or as any of a number of well-characterized fragments that include specific antigen-binding activity. Such fragments can be produced by digestion with various peptidases. Pepsin digests an antibody below the disulfide linkages in the hinge region to produce F(ab)′ 2 , a dimer of Fab which itself is a light chain joined to V H -C H 1 by a disulfide bond. The F(ab)′ 2 may be reduced under mild conditions to break the disulfide linkage in the hinge region, thereby converting the F(ab)′ 2 dimer into an Fab′ monomer.
  • the Fab′ monomer is essentially Fab with part of the hinge region (see Fundamental Immunology (Paul ed., 3d ed. 1993). While various antibody fragments are defined in terms of the digestion of an intact antibody, one of skill will appreciate that such fragments may be synthesized de novo either chemically or by using recombinant DNA methodology. Thus, the term antibody, as used herein, also includes antibody fragments either produced by the modification of whole antibodies, or those synthesized de novo using recombinant DNA methodologies (e.g., single chain Fv) or those identified using phage display libraries (see, e.g., McCafferty et al., Nature 348:552-554 (1990)).
  • aptamer refers to short oligonucleotides (e.g. deoxyribonucleotides), which fold into diverse and intricate molecular structures that bind with high affinity and specificity to proteins, peptides, and small molecules in a non-Watson Crick manner.
  • An aptamer can thus be used to detect or otherwise target nearly any molecule of interest, including a fibrotic pulmonary disease marker protein.
  • Methods of constructing and determining the binding characteristics of aptamers are well known in the art. For example, such techniques are described in U.S. Pat. Nos. 5,582,981, 5,595,877 and 5,637,459.
  • Aptamers are typically at least 5 nucleotides, 10, 20, 30 or 40 nucleotides in length, and can be composed of modified nucleic acids to improve stability. Flanking sequences can be added for structural stability, e.g., to form 3-dimensional structures in the aptamer. Aptamers can be selected in vitro from very large libraries of randomized sequences by the process of systemic evolution of ligands by exponential enrichment (SELEX as described in Ellington A D, Szostak J W (1990) In vitro selection of RNA molecules that bind specific ligands.
  • a “biomarker”, “marker protein” or “biomarker protein” as provided herein refers to any assayable characteristics or compositions that is used to identify, predict, or monitor a condition (e.g., a fibrotic pulmonary disease or lack thereof) or a therapy for said condition in a subject or sample.
  • a biomarker is, for example, a protein or combination of proteins whose presence, absence, or relative amount is used to identify a condition (e.g. IPF) or status of a condition (e.g. IPF) in a subject or sample.
  • Biomarkers identified herein are measured to determine levels, expression, activity, or to detect fragments, variants or homologs of said biomarkers.
  • Variants include amino acid or nucleic acid variants or post translationally modified variants.
  • the marker protein is a protein or fragment thereof as set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B.
  • the marker protein is a homolog of the protein listed in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B.
  • the marker proteins provided herein are identified by accession numbers referring to the corresponding amino acid and/or nucleic acid sequence of the individual marker proteins. Therefore, a person of ordinary skill in the art will immediately recognize the sequences of the marker proteins provided herein.
  • control level is meant the expression level of a particular biomarker(s) from a sample or subject lacking a disease (e.g. IPF), at a selected stage of a disease or disease state, or in the absence of a particular variable such as a therapeutic agent.
  • control level comprises a known amount of biomarker. Such a known amount correlates with an average level of subjects lacking a disease, at a selected stage of a disease or disease state, or in the absence of a particular variable such as a therapeutic agent.
  • a control level also includes the expression level of one or more biomarkers from one or more selected samples or subjects as described herein.
  • a control level includes an assessment of the expression level of one or more biomarkers in a sample from a subject that does not have a disease (e.g. IPF), is at a selected stage of progression of a disease (e.g. IPF), or has not received treatment for a disease.
  • Another exemplary control level includes an assessment of the expression level of one or more biomarkers in samples taken from multiple subjects that do not have a disease, are at a selected stage of progression of a disease, or have not received treatment for a disease.
  • control level includes the expression level of one or more biomarkers in a sample or subject in the absence of a therapeutic agent
  • the control sample or subject is optionally the same sample or subject to be tested before or after treatment with a therapeutic agent or is a selected sample or subject in the absence of the therapeutic agent.
  • a control level is an average expression level calculated from a number of subjects without a particular disease.
  • a control level also includes a known control level or value known in the art.
  • a biomarker is a protein or combination of proteins whose expression level in a subject or sample is indicative of a fibrotic pulmonary disease or a fibrotic pulmonary disease activity.
  • the expression level of a biomarker or a combination of a plurality of biomarkers may be increased or decreased compared to a control level.
  • the expression level of a biomarker or a combination of a plurality of biomarkers as provided herein may be increased or decreased in a subject compared to the expression level of the same subject at an earlier time point. Therefore, the expression level of a biomarker as provided herein may be indicative of a specific disease stage.
  • the biomarker may be indicative of the efficacy of treatment.
  • the expression level of a biomarker may be indicative of whether a patient is responsive to a treatment.
  • the biomarker may further be indicative of the activity of a disease, wherein the activity of a disease refers to the change of one or more biomarker expression levels over the course of the disease.
  • agonist refers to a substance capable of detectably increasing the expression or activity of a given gene or protein.
  • the agonist can increase expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the agonist.
  • expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.
  • inhibitor refers to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
  • the antagonist can decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more in comparison to a control in the absence of the antagonist. In certain instances, expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.
  • the pulmonary diseases contemplated herein can include any pulmonary disorders, lung fibrosis diseases, interstitial lung diseases, idiopathic interstitial pneumonias (BP), idiopathic pulmonary fibrosis, familial interstitial pneumonia (FIP), non-specific interstitial pneumonia (NSIP), hypersensitivity pneumonitis, acute respiratory distress syndrome (ARDS), scleroderma associated interstitial lung disease (SSc-ILD), Sarcoidosis, Beryllium disease, rheumatoid arthritis associated lung disorder, collagen vascular associated lung disorder, cigarette smoke associated lung disorders, Sjögren's syndrome, mixed connective tissue disease, etc.
  • BP idiopathic interstitial pneumonias
  • FIP familial interstitial pneumonia
  • NSIP non-specific interstitial pneumonia
  • ARDS acute respiratory distress syndrome
  • SSc-ILD scleroderma associated interstitial lung disease
  • Sarcoidosis Beryllium disease
  • rheumatoid arthritis associated lung disorder collagen
  • Pulmonary fibrotic conditions e.g., interstitial lung diseases (ILD) are characterized by shortness of breath, chronic coughing, fatigue and weakness, loss of appetite, and rapid weight loss. Pulmonary fibrosis is commonly linked to interstitial lung diseases (e.g., autoimmune disorders, viral infections or other microscopic injuries), but can be idiopathic. Fibrosis involves exchange of normal lung tissue with fibrotic tissue (scar tissue) that leads to reduced oxygen capacity.
  • interstitial lung diseases e.g., autoimmune disorders, viral infections or other microscopic injuries
  • IIP Idiopathic interstitial pneumonias
  • IIPs are a subset of diffuse interstitial lung diseases of unknown etiology (the term “idiopathic” indicates unknown origin). IIPs are characterized by expansion of the interstitial compartment (i.e., that portion of the lung parenchyma sandwiched between the epithelial and endothelial basement membranes) with an infiltrate of inflammatory cells. The inflammatory infiltrate is sometimes accompanied by fibrosis, either in the form of abnormal collagen deposition or proliferation of fibroblasts capable of collagen synthesis.
  • Idiopathic Pulmonary Fibrosis occurs in thousands of people worldwide with a doubling of prevalence over the past 10 years. Onset of IPF occurs around 50 to 70 years of age and starts with progressive shortness of breath and hypoxemia. IPF median survival is around 3-5 years and is to date untreatable. The etiology and pathogenesis of the condition is not well understood. About 5-20 percent of all cases of IPF have a family history and inheritance appears to be autosomal dominant. The clinical course of IPF is highly variable. Individuals diagnosed with IPF can experience a slow and steady decline, whereas others may decline more rapidly, thereby exhibiting a progressive form of idiopathic pulmonary fibrosis.
  • Patients may also experience periods of relative stability interrupted by periods of rapid decline (known as acute exacerbations).
  • a progressive form of idiopathic pulmonary fibrosis is characterized by the rapid decline of clinical and physical markers (e.g., FEV1, VC, FVC, DL CO as defined below).
  • Additional fibrotic pulmonary diseases include Acute Interstitial Pneumonia (AIP), Respiratory Bronchiolitis-associated Interstitial Lung Disease (RBILD), Desquamative Interstitial Pneumonia (DIP), Non-Specific Interstitial Pneumonia (NSIP), Bronchiolitis obliterans, with Organizing Pneumonia (BOOP).
  • AIP Acute Interstitial Pneumonia
  • RILD Respiratory Bronchiolitis-associated Interstitial Lung Disease
  • DIP Desquamative Interstitial Pneumonia
  • NIP Non-Specific Interstitial Pneumonia
  • BOP Bronchiolitis obliterans
  • AIP is a rapidly progressive and histologically distinct form of interstitial pneumonia.
  • the pathological pattern is an organizing form of diffuse alveolar damage (DAD) that is also found in acute respiratory distress syndrome (ARDS) and other acute interstitial pneumonias of known causes (see Clinical Atlas of Interstitial Lung Disease (2006 ed.) pp 61-63).
  • DAD diffuse alveolar damage
  • ARDS acute respiratory distress syndrome
  • ARDS acute respiratory distress syndrome
  • RBILD is characterized by inflammatory lesions of the respiratory bronchioles in cigarette smokers.
  • the histologic appearance of RBILD is characterized by the accumulation of pigmented macrophages within the respiratory bronchioles and the surrounding airspaces, variably, peribronchial fibrotic alveolar septal thickening, and minimal associated mural inflammation (see Wells et al. (2003) Sem Respir. Crit. Care Med . vol. 24).
  • DIP is a rare interstitial lung disease characterized by the accumulation of macrophages in large numbers in the alveolar spaces associated with interstitial inflammation and/or fibrosis.
  • the macrophages frequently contain light brown pigment. Lymphoid nodules are common, as is a sparse but distinct eosinophil infiltrate. DIP is most common in smokers (see Tazelaar et at (Sep. 21, 2010) Histopathology ).
  • NSIP is characterized pathologically by uniform interstitial inflammation and fibrosis appearing over a short period of time. NSIP differs from other interstitial lung diseases in that it has a generally good prognosis. In addition, the temporal uniformity of the parenchymal changes seen in NSIP contrasts greatly with the temporal heterogeneity of usual interstitial pneumonia (see Coche et al. (2001) Brit J Radiol 74:189).
  • BOOP unlike NSIP, can be fatal within days of first acute symptoms. It is characterized by rapid onset of acute respiratory distress syndrome; therefore, clinically, rapidly progressive BOOP can be indistinguishable from acute interstitial pneumonia. Histological features include clusters of mononuclear inflammatory cells that form granulation tissue and plug the distal airways and alveolar spaces. These plugs of granulation tissue may form polyps that migrate within the alveolar ducts or may be focally attached to the wall. (see White & Ruth-Saad (2007) Crit. Care Nurse 27:53).
  • Diagnostic indicators of pulmonary disorders include biopsy (e.g., VATS or surgical lung biopsy), high resolution computed tomography (HRTC) or breathing metrics, such as forced expiratory volume (FEV1), vital capacity (VC), forced vital capacity (FVC), and FEV1/FVC.
  • biopsy e.g., VATS or surgical lung biopsy
  • HRTC high resolution computed tomography
  • breathing metrics such as forced expiratory volume (FEV1), vital capacity (VC), forced vital capacity (FVC), and FEV1/FVC.
  • biomarkers e.g. protein biomarkers
  • therapeutic targets for ameliorating fibrotic pulmonary diseases.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a subject that has or is at risk for developing a fibrotic pulmonary disease includes (i) obtaining a biological sample from the subject and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in the biological sample.
  • the method includes selecting a subject that has or is at risk for developing a fibrotic pulmonary disease. The selected subject may be treated for fibrotic pulmonary disease.
  • the subject is not treated for fibrotic pulmonary disease.
  • the subject may be part of a plurality of subjects participating in a clinical trial. Wherein the subject is part of a clinical trial, the selecting is at least part based on the determining of an expression level as provided herein.
  • a fibrotic pulmonary disease marker protein is a biomarker protein useful to identify, predict, or monitor a fibrotic pulmonary disease or lack thereof or a therapy for fibrotic pulmonary disease in a subject or sample.
  • determining an expression level of a fibrotic pulmonary disease marker protein described herein includes determining the level of one or more fibrotic pulmonary disease marker proteins in a sample (e.g. patient biological sample such as a blood-derived biological sample).
  • a sample e.g. patient biological sample such as a blood-derived biological sample.
  • the expression level of a plurality of fibrotic pulmonary disease marker proteins is determined.
  • the level of at least two (e.g. 3, 4, 5, 6, 7, 8, 9, 10 etc.) fibrotic pulmonary disease marker proteins is determined and the at least two fibrotic pulmonary disease marker proteins are independently different.
  • the fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia. In embodiments, the fibrotic pulmonary disease is a progressive form of idiopathic pulmonary fibrosis. In other embodiments, the fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • a progressive fibrotic pulmonary disease maker protein is a biomarker protein indicative of a fibrotic pulmonary disease patient having or being at risk of developing progressive fibrotic pulmonary disease (e.g., a progressive form of a fibrotic pulmonary disease). Thus, in some embodiments, the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • a progressive fibrotic pulmonary disease is a disease wherein certain clinical or physiological parameters decline over the course of the disease. Commonly used parameters to determine fibrotic pulmonary disease progression include for example, breathing metrics, such as forced expiratory volume (FEV1), vital capacity (VC), forced vital capacity (FVC), FEV1/FVC and diffusing capacity of carbon monoxide (DL CO ).
  • breathing metrics such as forced expiratory volume (FEV1), vital capacity (VC), forced vital capacity (FVC), FEV1/FVC and diffusing capacity of carbon monoxide (DL CO ).
  • FEV1 forced expiratory volume
  • VC vital capacity
  • FVC forced vital capacity
  • FVC forced vital capacity
  • FEV1/FVC diffusing capacity of carbon monoxide
  • DL CO diffusing capacity of carbon monoxide
  • a control level may be the FVC of the same patient measured at an earlier stage of the fibrotic pulmonary disease or the FVC calculated from a number of subjects lacking the fibrotic pulmonary disease.
  • the FVC of a progressive fibrotic pulmonary disease patient is at least 5% less than a control level.
  • the FVC of a progressive fibrotic pulmonary disease patient is about 5% less than a control level. In some embodiments, the FVC of a progressive fibrotic pulmonary disease patient is at least 10% less than a control level. In other embodiments, the FVC of a progressive fibrotic pulmonary disease patient is about 10% less than a control level.
  • Another parameter of progressive fibrotic pulmonary disease is a decline in the 6-minute walk test distance (6MWD).
  • 6MWD 6-minute walk test distance
  • a fibrotic pulmonary disease patient showing a decline of more than 50 meters in the 6MWD compared to a control distance may be considered a progressive fibrotic pulmonary disease patient.
  • a control distance refers to the 6MWD of the same patient measured at an earlier stage of the fibrotic pulmonary disease or the 6MWD calculated from a number of subjects lacking the fibrotic pulmonary disease.
  • the decline in the 6MWD is at least 30 meters. In other embodiments, the decline in the 6MWD is about 50 meters.
  • a fibrotic pulmonary disease patient showing a decline of more than 15% in DL CO compared to a control level may be considered a progressive fibrotic pulmonary disease patient.
  • a control level refers to the DL CO of the same patient measured at an earlier stage of the fibrotic pulmonary disease or the DL CO calculated from a number of subjects lacking the fibrotic pulmonary disease.
  • the DL CO of a progressive fibrotic pulmonary disease patient is at least 10% less compared to a control level.
  • the DL CO of a progressive fibrotic pulmonary disease patient is about 15% less than a control level.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • the methods provided herein including embodiments thereof further include treating a subject for fibrotic pulmonary diseases.
  • the expression level of one or more fibrotic pulmonary disease marker proteins is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1B is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 2A is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 2B is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 4A is determined.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 4B is determined.
  • the expression levels of the one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B may be increased or decreased in a fibrotic pulmonary disease patient.
  • the expression levels of the one or more fibrotic pulmonary disease marker proteins set forth in Table 2A or Table 2B may be increased or decreased in a fibrotic pulmonary disease patient.
  • the expression levels of the one or more fibrotic pulmonary disease marker proteins set forth in Table 4A or Table 4B may be increased or decreased in a fibrotic pulmonary disease patient.
  • the one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 2A or 4A is increased. In other embodiments, the one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 2A or 4A is decreased. In some embodiments, the one or more fibrotic pulmonary disease marker proteins set forth in Table 1B, 2B or 4B is increased. In other embodiments, the one or more fibrotic pulmonary disease marker proteins set forth in Table 1B, 2B or 4B is decreased.
  • the expression level of the fibrotic pulmonary disease marker protein set forth in Table 1A is elevated relative to a standard control. In other embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 1B is decreased relative to a standard control. In some embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 2A is elevated relative to a standard control. In other embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 2B is decreased relative to a standard control. In some embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 4A is elevated relative to a standard control. In other embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 4B is decreased relative to a standard control.
  • a treatment regimen for a fibrotic pulmonary disease patient with modulated expression levels of one or more fibrotic pulmonary disease marker proteins as disclosed herein may be administering to the patient an effective amount of a modulator affecting the one or more increased or decreased biomarker protein expression levels. Therefore, in some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1A or 1B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2A or 2B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4A or 4B.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2B.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4B.
  • the modulator is an antagonist.
  • the antagonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • the modulator is an agonist.
  • the agonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • the agonist is a fibrotic pulmonary disease marker protein set forth in Table 1A or 1B.
  • the agonist is a fibrotic pulmonary disease marker protein set forth in Table 2A or 2B.
  • the agonist is a fibrotic pulmonary disease marker protein set forth in Table 4A or 4B.
  • the methods provided herein may include combinatorial treatment of a fibrotic pulmonary disease patient with a modulator of one or more fibrotic pulmonary disease marker proteins and a fibrotic pulmonary disease treatment.
  • the method includes administering to the subject an effective amount of a further therapeutic agent.
  • Exemplary therapeutic agents include, but are not limited to, the agents selected from the group consisting of steroids (including but not limited to prednisolone), cytotoxic agents (including but not limited to azathioprine and cyclophosphamide), bardoxolone, LPA agonists (including but not limited to AM152); Torisel (temsirolimus); PI3K inhibitors; pentraxin or serum amyloid P (including but not limited to Pentraxin-2 (PTX-2 or PRM-151)); MEK inhibitors (including but not limited to ARRY-162 and ARRY-300); p38 inhibitors; PAI-1 inhibitors (including but not limited to Tiplaxtinin); agents that reduce the activity of transforming growth factor-beta (TGF- ⁇ ) (including but not limited to GC-1008 (Genzyme/MedImmune); lerdelimumab (CAT-152; Trabio, Cambridge Antibody); metelimumab (CAT-192, Cambridge Antibody,); LY-21572
  • the therapeutic agent is an anti-fibrotic drug. In some embodiments, the therapeutic agent is an idiopathic pulmonary fibrosis drug. In other embodiment, the idiopathic pulmonary fibrosis drug is a mucolytic drug.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 1A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to the standard control indicates that the subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on the expression level in step (ii), determining whether the subject has or is at risk for developing a fibrotic pulmonary disease.
  • the method includes selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • the fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • the one or more fibrotic pulmonary disease marker proteins is a progressive fibrotic pulmonary disease marker protein.
  • the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B is detected from a biological sample of the subject.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • the methods provided herein include treating for fibrotic pulmonary disease.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1A or 1B.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1A.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1B.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2A.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4B.
  • the modulator is an antagonist. In other embodiments, the antagonist is a peptide, small molecule, nucleic acid, antibody or aptamer. In one embodiment, the modulator is an agonist. In one embodiment, the agonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • the methods provided herein may further include administering to the subject an effective amount of a further therapeutic agent (e.g., as described above).
  • a further therapeutic agent e.g., as described above.
  • the therapeutic agent is an idiopathic pulmonary fibrosis drug.
  • the idiopathic pulmonary fibrosis drug is a mucolytic drug.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a fibrotic pulmonary disease patient (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 1A or Table 1B relative to the standard control indicates that the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • the determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients. In embodiments, the determining whether the expression level is modulated relative to a standard control includes determining whether the expression level is elevated or suppressed relative to an expression level of the same fibrotic pulmonary disease marker protein in other fibrotic pulmonary disease patients. In embodiments, the determining whether the expression level is modulated relative to a standard control includes determining whether the expression level is elevated or suppressed relative to an expression level of a different fibrotic pulmonary disease marker protein in the patient. In some embodiments, the fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia. In other embodiments, the fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • an increased expression level of a fibrotic pulmonary disease marker protein in Table 1A relative to a standard control indicates an increased risk for progression of the fibrotic pulmonary disease.
  • a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1A relative to a standard control indicates an decreased risk for progression of the fibrotic pulmonary disease.
  • an increased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to a standard control indicates an increased risk for progression of the fibrotic pulmonary disease.
  • a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to a standard control indicates an decreased risk for progression of the fibrotic pulmonary disease.
  • the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, wherein when the second expression level of a protein set forth in Table 1A is greater than the first level of a protein set forth in Table 1A; or wherein when the second expression level of a protein set forth in Table 1B is smaller than the first level of a protein set forth in Table 1B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • the patient at risk for progression of the fibrotic pulmonary disease may have received treatment for the fibrotic pulmonary disease prior to the determining in step (i). Where the patient at risk for progression of the fibrotic pulmonary disease has received treatment for the fibrotic pulmonary disease prior to the determining in step (i) the treatment may be altered after the determining in step (i) and before the determining in step (ii). Alternatively, the patient at risk for progression of the fibrotic pulmonary disease may not have received treatment for the fibrotic pulmonary disease prior to the determining in step (i). Where the patient at risk for progression of the fibrotic pulmonary disease has not received treatment for the fibrotic pulmonary disease prior to the determining in step (i) the patient may receive treatment after the determining in step (i).
  • the method includes administering a fibrotic pulmonary disease treatment after the determining in step (i). In some embodiments, the method further includes determining a rate of progression of the fibrotic pulmonary disease in the patient based on the comparing. In some embodiments, the method further includes predicting a rate of progression of the fibrotic pulmonary disease in the patient based on the comparing.
  • the determining the first expression level of a protein set forth in Table 1A or Table 1B and the second expression level of a protein set forth in Table 1A or Table 1B includes normalizing the first expression level of a protein set forth in Table 1A or Table 1B and the second expression level of a protein set forth in Table 1A or Table 1B to a protein expressed from a standard gene in the patient.
  • the standard gene is a so-called housekeeping gene, as is commonly known in the art, such as GAPDH or beta-actin.
  • the standard gene is non-differentially expressed. Where the standard gene is non-differentially expressed, the expression level of the standard gene remains unchanged over the time course of the disease.
  • the first expression level is detected from a first biological sample of the subject and the second expression level is detected from a second biological sample of the subject.
  • the first biological sample is a first bodily fluid sample and the second biological sample is a second bodily fluid sample.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining the fibrotic pulmonary disease activity in the patient.
  • the expression level of a fibrotic pulmonary disease marker protein in Table 1A is increased relative to the standard control.
  • the expression level of a fibrotic pulmonary disease marker protein in Table 1B is decreased relative to the standard control.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, thereby determining the fibrotic pulmonary disease activity in the patient.
  • the method includes administering a fibrotic pulmonary disease treatment after the determining in step (i).
  • the method includes determining a change in a fibrotic pulmonary disease activity.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes administering to the subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B, thereby treating a fibrotic pulmonary disease in the subject.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1A.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2A.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 1B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 2B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 4B. In other embodiments, the modulator is an antagonist.
  • the antagonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • the modulator is an agonist.
  • the agonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 1A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 1B relative to a standard control; and (ii) when an elevated expression level of the fibrotic pulmonary disease marker protein of Table 1A or a decreased expression level of the fibrotic pulmonary disease marker protein of Table 1B is found relative to the standard control, administering to the subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 1A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 1B, thereby treating the subject.
  • the fibrotic pulmonary disease treatment is a mucolytic drug.
  • one or more fibrotic pulmonary disease marker proteins are set forth in Table 1A or Table 1B.
  • the one or more fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B is a protein set forth in Table 2A or Table 2B.
  • the one or more fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B is a protein set forth in Table 4A or Table 4B.
  • the one or more fibrotic pulmonary disease marker protein is set forth in Table 2A.
  • the one or more fibrotic pulmonary disease marker protein is set forth in Table 2B.
  • the one or more fibrotic pulmonary disease marker protein is set forth in Table 4A.
  • the one or more fibrotic pulmonary disease marker protein is set forth in Table 4B.
  • the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • the progressive fibrotic pulmonary disease is a progressive form of idiopathic pulmonary fibrosis.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A is determined. In other embodiments, an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3B is determined. In embodiments, the risk for developing a progressive fibrotic pulmonary disease is increased relative to a standard control. In embodiments, the risk for developing a progressive fibrotic pulmonary disease is decreased relative to a standard control.
  • the expression levels of the one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B may be increased or decreased in a fibrotic pulmonary disease patient. In some embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 3A is elevated relative to a standard control. In other embodiments, the expression level of the fibrotic pulmonary disease marker protein set forth in Table 3B is decreased relative to a standard control.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3A or 3B. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3A. In some embodiments, the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3B. Thus, the method includes administering to the subject an effective amount of a further therapeutic agent.
  • the therapeutic agent is an idiopathic pulmonary fibrosis drug. In other embodiment, the idiopathic pulmonary fibrosis drug is a mucolytic drug.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in a subject that has or is at risk for developing a fibrotic pulmonary disease includes (i) obtaining a biological sample from the subject, and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in the biological sample.
  • the method includes selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • the fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • the one or more fibrotic pulmonary disease marker proteins is a progressive fibrotic pulmonary disease marker protein.
  • the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • the progressive fibrotic pulmonary disease is a progressive form of idiopathic pulmonary fibrosis.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B is detected from a biological sample of the subject.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • the methods provided herein include treating for fibrotic pulmonary disease.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3A or 3B.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3A.
  • the method includes administering to the subject an effective amount of a modulator of the fibrotic pulmonary disease marker protein set forth in Table 3B.
  • the methods provided herein may further include administering to the subject an effective amount of a further therapeutic agent.
  • the therapeutic agent is an idiopathic pulmonary fibrosis drug.
  • the idiopathic pulmonary fibrosis drug is a mucolytic drug.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject, (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 3A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to the standard control indicates that the subject has or is at risk of developing a fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the subject has or is at risk for developing a fibrotic pulmonary disease.
  • the determining the first expression level of a protein set forth in Table 3A or Table 3B and the second expression level of a protein set forth in Table 3A or Table 3B includes normalizing the first expression level of a protein set forth in Table 3A or Table 3B and the second expression level of a protein set forth in Table 3A or Table 3B to a protein expressed from a standard gene in the patient.
  • the standard gene is a so-called housekeeping gene, as is commonly known in the art, such as GAPDH or beta-actin.
  • the standard gene is non-differentially expressed. Where the standard gene is non-differentially expressed, the expression level of the standard gene remains unchanged over the time course of the disease.
  • the first expression level is detected from a first biological sample of the subject and the second expression level is detected from a second biological sample of the subject.
  • the first biological sample is a first bodily fluid sample and the second biological sample is a second bodily fluid sample.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 3A or 3B in a fibrotic pulmonary disease patient, (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 3A or 3B relative to the standard control indicates that the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease, and (iii) based at least in part on the expression level in step (ii), determining whether the fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • the determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients. In embodiments, the determining whether the expression level is modulated relative to a standard control includes determining whether the expression level is elevated or suppressed relative to an expression level of the same fibrotic pulmonary disease marker protein in other fibrotic pulmonary disease patients. In embodiments, the determining whether the expression level is modulated relative to a standard control includes determining whether the expression level is elevated or suppressed relative to an expression level of a different fibrotic pulmonary disease marker protein in the patient. In some embodiments, the fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia. In other embodiments, the fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • an increased expression level of a fibrotic pulmonary disease marker protein in Table 3A relative to a standard control indicates an increased risk for progression of the fibrotic pulmonary disease.
  • a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3A relative to a standard control indicates an decreased risk for progression of the fibrotic pulmonary disease.
  • an increased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to a standard control indicates an increased risk for progression of the fibrotic pulmonary disease.
  • a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to a standard control indicates an decreased risk for progression of the fibrotic pulmonary disease.
  • the subject has or is at risk for developing a progressive fibrotic pulmonary disease.
  • the progressive fibrotic pulmonary disease is idiopathic pulmonary fibrosis.
  • the progressive fibrotic pulmonary disease is a progressive form of idiopathic pulmonary fibrosis.
  • the biological sample is a blood-derived biological sample of the subject.
  • the blood-derived biological sample is whole blood, serum or plasma.
  • the biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point, (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point, (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, wherein when the second expression level of a protein set forth in Table 3A is greater than the first level of a protein set forth in Table 3A, or wherein when the second expression level of a protein set forth in Table 3B is smaller than the first level of a protein set forth in Table 3B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • the patient at risk for progression of the fibrotic pulmonary disease may have received treatment for the fibrotic pulmonary disease prior to the determining in step (i). Where the patient at risk for progression of the fibrotic pulmonary disease has received treatment for the fibrotic pulmonary disease prior to the determining in step (i) the treatment may be altered after the determining in step (i) and before the determining in step (ii). Alternatively, the patient at risk for progression of the fibrotic pulmonary disease may not have received treatment for the fibrotic pulmonary disease prior to the determining in step (i). Where the patient at risk for progression of the fibrotic pulmonary disease has not received treatment for the fibrotic pulmonary disease prior to the determining in step (i) the patient may receive treatment after the determining in step (i).
  • the method includes administering a fibrotic pulmonary disease treatment after the determining in step (i). In some embodiments, the method further includes determining a rate of progression of the fibrotic pulmonary disease in the patient based on the comparing.
  • the determining the first expression level of a protein set forth in Table 3A or Table 3B and the second expression level of a protein set forth in Table 3A or Table 3B includes normalizing the first expression level of a protein set forth in Table 3A or Table 3B and the second expression level of a protein set forth in Table 3A or Table 3B to a protein expressed from a standard gene in the patient.
  • the standard gene is a so-called housekeeping gene, as is commonly known in the art, such as GAPDH or beta-actin.
  • the standard gene is non-differentially expressed. Where the standard gene is non-differentially expressed, the expression level of the standard gene remains unchanged over the time course of the disease.
  • the first expression level is detected from a first biological sample of the subject and the second expression level is detected from a second biological sample of the subject.
  • the first biological sample is a first bodily fluid sample and the second biological sample is a second bodily fluid sample.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in the patient; and (iii) based at least in part on the expression level in step (ii), determining the fibrotic pulmonary disease activity in the patient.
  • the expression level of a fibrotic pulmonary disease marker protein in Table 3A is increased relative to the standard control.
  • the expression level of a fibrotic pulmonary disease marker protein in Table 3B is decreased relative to the standard control.
  • a method of determining a fibrotic pulmonary disease activity in a patient includes (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point, (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point, (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, thereby determining the fibrotic pulmonary disease activity in the patient.
  • the method includes determining a change in a fibrotic pulmonary disease activity.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes administering to the subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B, thereby treating a fibrotic pulmonary disease in the subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof includes (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 3A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 3B relative to a standard control, and (ii) when an elevated expression level of the fibrotic pulmonary disease marker protein of Table 3A or a decreased expression level of the fibrotic pulmonary disease marker protein of Table 3B is found relative to the standard control, administering to the subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 3A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 3B, thereby treating the subject.
  • the determining whether the expression level is modulated relative to a standard control includes determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients. Therefore a standard control as referred to herein may include or may be an average value gathered from a population of pulmonary disease patients. In other embodiments, a standard control is an average value gathered from a population of normal patients.
  • kits for detection of fibrotic pulmonary disease marker proteins or fragments thereof in a subject can be for personal use or provided to medical professionals.
  • the kit can be a kit for diagnosing or prognosing a fibrotic pulmonary disease, or for monitoring the progression of disease or the efficacy of treatment.
  • a kit in one aspect, includes a marker protein binding agent (e.g., an aptamer, optionally labeled) capable of binding to a substance within a biological sample (e.g., whole blood, serum or plasma) from a human subject having or at risk of developing a fibrotic pulmonary disease, wherein the substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B); and a detecting reagent or a detecting apparatus capable of indicating binding of the marker protein binding agent to the substance.
  • a marker protein binding agent e.g., an aptamer, optionally labeled
  • the kit can further include assay containers (tubes), buffers, or enzymes necessary for carrying out the detection assay.
  • the kit further includes a sample collection device for collecting a sample from a subject.
  • the human subject has a fibrotic pulmonary disease.
  • a kit in another aspect, includes a marker protein binding agent capable of binding to a substance within a biological sample from a human subject having a fibrotic pulmonary disease, wherein the substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B); and a detecting reagent or a detecting apparatus capable of indicating binding of the marker protein binding agent to the substance.
  • the kit includes components to examine more than one fibrotic pulmonary disease marker protein or fragment thereof.
  • the kit can include more than one marker protein binding agent capable of binding to one or more fibrotic pulmonary disease marker proteins or fragments thereof set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B.
  • the kit includes a plurality of marker protein binding agents. Where the kit includes a plurality of marker protein binding agents a plurality of fibrotic pulmonary disease marker proteins or fragments thereof (e.g., as set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B) are detected.
  • the kit will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the testing agent, can be suitably reacted or aliquoted. Kits can also include components for comparing results such as a suitable control sample, for example a positive and/or negative control.
  • the kit can also include a collection device for collecting and/or holding the sample from the subject.
  • the collection device can include a sterile swab or needle (for collecting blood), and/or a sterile tube (e.g., for holding the swab or a bodily fluid sample).
  • a complex in vitro includes a marker protein binding agent bound to a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B), wherein the fibrotic pulmonary disease marker protein is extracted from a human subject having or at risk of developing a fibrotic pulmonary disease.
  • the subject has a fibrotic pulmonary disease.
  • a complex in vitro includes a marker protein binding agent bound to a fibrotic pulmonary disease marker protein or fragment thereof set forth in the tables provided herein (e.g., Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B), wherein the fibrotic pulmonary disease marker protein is extracted from a human subject having a fibrotic pulmonary disease.
  • the methods provided herein include the step of determining (detecting) an expression level of a fibrotic pulmonary disease marker protein or fragment thereof.
  • Methods for detecting and identifying proteins and their interactions with other proteins or nucleic acid molecules involve conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature (see, e.g., Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition 1989, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Animal Cell Culture, R. I. Freshney, ed., 1986).
  • Determining an expression level of a protein” or “determining a level of expression of a protein” as provided herein includes methods and technologies well known in the art.
  • capture arrays for expression profiling may be used to determine an expression level of a protein.
  • Capture arrays employ high affinity capture reagents, such as conventional antibodies, single domains, engineered scaffolds, peptides or nucleic acid aptamers, to bind and detect specific target ligands in high throughput manner.
  • Antibody arrays have the required properties of specificity and acceptable background, and some are available commercially (BD Biosciences, San Jose, Calif.; Clontech, Mountain View, Calif.; BioRad; Sigma, St. Louis, Mo.).
  • Antibodies for capture arrays are made either by conventional immunization (polyclonal sera and hybridomas), or as recombinant fragments, usually expressed in E. coli , after selection from phage or ribosome display libraries (Cambridge Antibody Technology, Cambridge, UK; BioInvent, Lund, Sweden; Affitech, Walnut Creek, Calif.; Biosite, San Diego, Calif.).
  • Fab and scFv fragments single V-domains from camelids or engineered human equivalents (Domantis, Waltham, Mass.) are optionally useful in arrays.
  • scaffold refers to ligand-binding domains of proteins, which are engineered into multiple variants capable of binding diverse target molecules with antibody-like properties of specificity and affinity.
  • the variants are produced in a genetic library format and selected against individual targets by phage, bacterial or ribosome display.
  • ligand-binding scaffolds or frameworks include Affibodies based on S. aureus protein A (Affibody, Bromma, Sweden), Trinectins based on fibronectins (Phylos, Lexington, Mass.) and Anticalins based on the lipocalin structure (Pieris Proteolab, Freising-Weihenstephan, Germany). These are used on capture arrays in a similar fashion to antibodies and have advantages of robustness and ease of production.
  • Nonprotein capture molecules notably the nucleic acid aptamers which bind protein ligands with high specificity and affinity, are also used in arrays (SomaLogic, Boulder, Colo.).
  • Aptamers are selected from libraries of oligonucleotides by the SelexTM procedure (SomaLogic, Boulder, Colo.) and their interaction with protein is enhanced by covalent attachment, through incorporation of brominated deoxyuridine and UV-activated crosslinking (photoaptamers). Photocrosslinking to ligand reduces the cross reactivity of aptamers due to the specific steric requirements.
  • Aptamers have the advantages of ease of production by automated oligonucleotide synthesis and the stability and robustness of DNA; on photoaptamer arrays, universal fluorescent protein stains are used to detect binding.
  • Protein analytes binding to antibody arrays are detected directly or indirectly, for example, via a secondary antibody. Direct labeling is used for comparison of different samples with different colors. Where pairs of antibodies directed at the same protein ligand are available, sandwich immunoassays provide high specificity and sensitivity and are therefore the method of choice for low abundance proteins such as cytokines; they also give the possibility of detection of protein modifications. Label-free detection methods, including mass spectrometry, surface plasmon resonance and atomic force microscopy, avoid alteration of ligand. What is required from any method is optimal sensitivity and specificity, with low background to give high signal to noise. Since analyte concentrations cover a wide range, sensitivity has to be tailored appropriately.
  • Proteins of interest are frequently those in low concentration in body fluids and extracts, requiring detection in the pg range or lower, such as cytokines or the low expression products in cells.
  • An alternative to an array of capture molecules is one made through molecular imprinting technology, in which peptides (e.g., from the C-terminal regions of proteins) are used as templates to generate structurally complementary, sequence-specific cavities in a polymerizable matrix; the cavities can then specifically capture (denatured) proteins that have the appropriate primary amino acid sequence (ProteinPrintTM, Aspira Biosystems, Burlingame, Calif.).
  • ProteinChip® array (Ciphergen, Fremont, Calif.), in which solid phase chromatographic surfaces bind proteins with similar characteristics of charge or hydrophobicity from mixtures such as plasma or tumor extracts, and SELDI-TOF mass spectrometry is used to detection the retained proteins.
  • determining (detecting) an expression level of a fibrotic pulmonary disease marker protein or fragment thereof as provided herein includes contacting a fibrotic pulmonary disease marker protein with a marker protein binding agent.
  • a “marker protein binding agent” as provided herein refers to a substance capable of binding a fibrotic pulmonary disease marker protein.
  • the marker protein binding agent may be a nucleic acid or a protein.
  • the marker protein binding agent is an aptamer.
  • the marker protein binding agent is peptide.
  • the marker protein binding agent is a small molecule.
  • the marker protein binding agent is an antibody.
  • the fibrotic pulmonary disease marker protein or fragment thereof is contacted with a marker protein binding agent in a biological sample (e.g., whole blood, serum or plasma).
  • the marker protein binding agent includes a detectable moiety.
  • the detectable moiety is a fluorescent moiety.
  • the marker protein binding agent includes a capturing moiety.
  • a “capturing moiety” refers to a protein or nucleic acid, which is covalently, through a linker or a chemical bond, or noncovalently attached to the marker protein binding agent and is capable of interacting with a capturing agent.
  • An example of a capturing moiety useful for the methods provided herein is biotin.
  • the capturing moiety is biotin.
  • the capturing moiety is a cleavable capturing moiety.
  • the capturing moiety is photocleavable biotin.
  • a “capturing agent” as provided herein refers to an agent capable of binding a capturing moiety.
  • the interaction between the capturing moiety and the capturing agent may be a high affinity interaction, wherein the capturing moiety and the capturing agent bind to each other (e.g., biotin, streptavidin).
  • An example of a capturing agent useful for the methods provided herein are streptavidin coated beads.
  • the capturing agent is a streptavidin coated bead.
  • any suitable affinity binding pairs known in the art may be used as capturing moiety and capturing agent in the methods provided herein.
  • the capturing moiety may be an antibody and the capturing agent may be an antigen-coated bead.
  • the capturing moiety is biotin and the capturing agent is a streptavidin coated bead.
  • the marker protein binding agent may bind non-covalently to the fibrotic pulmonary disease marker protein through ionic, van der Waals, electrostatic or hydrogen bonds.
  • a disease marker-protein binding agent complex is formed.
  • the methods provided herein including embodiments thereof include detecting the disease marker-protein binding agent complex, thereby determining the expression level of a fibrotic pulmonary disease marker protein or fragment thereof in a biological sample.
  • the determining includes (a) contacting a fibrotic pulmonary disease marker protein with a marker protein binding agent in the biological sample, thereby forming a disease marker protein-binding agent complex; and (b) detecting the disease marker protein-binding agent complex.
  • the disease marker protein-binding agent complex may be separated from the sample and unbound components contained therein by contacting the disease marker protein-binding agent complex with a capturing agent as described above (e.g., streptavidin-coated beads).
  • a capturing agent as described above (e.g., streptavidin-coated beads).
  • the detecting includes contacting the disease marker protein-binding agent complex with a capturing agent, thereby forming a captured disease marker protein-binding agent complex.
  • the captured disease marker protein-binding agent complex may be washed to remove any unbound components.
  • the fibrotic pulmonary disease marker protein or fragment thereof may be contacted with a tagging moiety.
  • a “tagging moiety” as provided herein is a composition capable of non-covalently binding to the fibrotic pulmonary disease marker protein or fragment thereof.
  • the tagging moiety is biotin.
  • the tagging moiety may bind through high affinity interaction with a tagging agent (e.g., streptavidin).
  • a tagging agent e.g., streptavidin
  • the fibrotic pulmonary disease marker protein or fragment thereof is contacted with a tagging moiety after the formation of a captured disease marker protein-binding agent complex.
  • the fibrotic pulmonary disease marker protein or fragment thereof is contacted with a tagging moiety before the formation of a captured disease marker protein-binding agent complex. In embodiments, the fibrotic pulmonary disease marker protein or fragment thereof is contacted with a tagging moiety at the same time as the formation of a captured disease marker protein-binding agent complex. In embodiments, the detecting further includes (1) contacting the captured disease marker protein-binding agent complex with a tagging moiety; thereby forming a tagged disease marker protein-binding agent complex; and (2) separating the tagged disease marker protein-binding agent complex from the biological sample.
  • the detecting further includes after the separating of step (2) separating the capturing binding agent from the tagged disease marker protein-binding agent complex, thereby forming a cleaved disease marker protein-binding agent complex.
  • the cleaved disease marker protein-binding agent complex may be contacted with a tagging agent (e.g., streptavidin-coated beads) and the tagging moiety (e.g., biotin) bound to the fibrotic pulmonary disease marker protein or fragment thereof may form a high affinity interaction with the tagging agent.
  • a tagging agent e.g., streptavidin-coated beads
  • the tagging moiety e.g., biotin bound to the fibrotic pulmonary disease marker protein or fragment thereof
  • the cleaved disease marker protein-binding agent complex may be captured by a tagging agent (e.g., streptavidin-coated beads) and the marker protein binding agent may be subsequently separated, (e.g., eluted by affinity chromatography) from the cleaved disease marker protein-binding agent complex.
  • the detecting further includes (3) separating the marker protein binding agent from the cleaved disease marker protein-binding agent complex; thereby forming a released marker protein binding agent; and (4) determining an amount of released marker protein binding agent.
  • the marker protein binding agent e.g., aptamer
  • the fibrotic pulmonary disease marker proteins as provided herein are applicable to all methods, kits and compositions described herein.
  • the expression level of one or more fibrotic pulmonary disease marker proteins may be determined (detected).
  • the expression level of at least one fibrotic pulmonary disease marker protein is determined (detected).
  • the expression level of a plurality e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20
  • the expression level of a combination of any one of the fibrotic pulmonary disease marker proteins provided herein is determined (detected).
  • the expression level of a combination of fibrotic pulmonary disease marker proteins set forth in Table 4A and/or Table 4B may be determined (detected) in the methods, kits or compositions provided herein.
  • the fibrotic pulmonary disease marker protein is a2-Macroglobulin, PUR8, iC3b, C4b, CAPG, PARC, Cathepsin H, Discoidin domain receptor 2, sICAM-5, LKHA4, MMP-7, MMP-9, NXPH1, OLR1, PTK6, or calgranulin B.
  • the fibrotic pulmonary disease marker protein is a2-Macroglobulin, PUR8, iC3b, C4b, CAPG, PARC, Cathepsin H, Discoidin domain receptor 2, sICAM-5, LKHA4, MMP-7, MMP-9, NXPH1, OLR1, PTK6, and calgranulin B.
  • the fibrotic pulmonary disease marker protein is a2-Macroglobulin.
  • the fibrotic pulmonary disease marker protein is PUR8.
  • the fibrotic pulmonary disease marker protein is iC3b.
  • the fibrotic pulmonary disease marker protein is C4b.
  • the fibrotic pulmonary disease marker protein is CAPG.
  • the fibrotic pulmonary disease marker protein is PARC. In embodiments, the fibrotic pulmonary disease marker protein is Cathepsin H. In embodiments, the fibrotic pulmonary disease marker protein is Discoidin domain receptor 2. In embodiments, the fibrotic pulmonary disease marker protein is sICAM-5. In embodiments, the fibrotic pulmonary disease marker protein is LKHA4. In embodiments, the fibrotic pulmonary disease marker protein is MMP-7. In embodiments, the fibrotic pulmonary disease marker protein is MMP-9. In embodiments, the fibrotic pulmonary disease marker protein is NXPH1. In embodiments, the fibrotic pulmonary disease marker protein is OLR1. In embodiments, the fibrotic pulmonary disease marker protein is PTK6.
  • the fibrotic pulmonary disease marker protein is calgranulin B.
  • the expression level of a2-Macroglobulin, PUR8, iC3b, C4b, CAPG, PARC, Cathepsin H, Discoidin domain receptor 2, sICAM-5, LKHA4, MMP-7, MMP-9, NXPH1, OLR1, PTK6, or calgranulin B is determined.
  • the expression level of a2-Macroglobulin, PUR8, iC3b, C4b, CAPG, PARC, Cathepsin H, Discoidin domain receptor 2, sICAM-5, LKHA4, MMP-7, MMP-9, NXPH1, OLR1, PTK6, and calgranulin B is determined.
  • the expression level of a2-Macroglobulin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PUR8 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of iC3b and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of C4b and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CAPG and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PARC and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Cathepsin H and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Discoidin domain receptor 2 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of sICAM-5 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of LKHA4 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of MMP-7 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of MMP-9 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of NXPH1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of OLR1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PTK6 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of calgranulin B and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the fibrotic pulmonary disease marker protein is AMPK a2b2g1, CAMK2A, CAMK2B, CAMK2D, COMMD7, FER, FYN, Integrin a1b1, LYNB, METAP1, MMP-3, PDPK1, phosphoglycerate kinase 1, SHC1, or SRCN1.
  • the fibrotic pulmonary disease marker protein is AMPK a2b2g1, CAMK2A, CAMK2B, CAMK2D, COMMD7, FER, FYN, Integrin a1b1, LYNB, METAP1, MMP-3, PDPK1, phosphoglycerate kinase 1, SHC1, and SRCN1.
  • the fibrotic pulmonary disease marker protein is AMPK a2b2g1. In embodiments, the fibrotic pulmonary disease marker protein is CAMK2A. In embodiments, the fibrotic pulmonary disease marker protein is CAMK2B. In embodiments, the fibrotic pulmonary disease marker protein is CAMK2D. In embodiments, the fibrotic pulmonary disease marker protein is COMMD7. In embodiments, the fibrotic pulmonary disease marker protein is FER. In embodiments, the fibrotic pulmonary disease marker protein is FYN. In embodiments, the fibrotic pulmonary disease marker protein is Integrin a1b1. In embodiments, the fibrotic pulmonary disease marker protein is LYNB.
  • the fibrotic pulmonary disease marker protein is METAP1. In embodiments, the fibrotic pulmonary disease marker protein is MMP-3. In embodiments, the fibrotic pulmonary disease marker protein is PDPK1. In embodiments, the fibrotic pulmonary disease marker protein is phosphoglycerate kinase 1. In embodiments, the fibrotic pulmonary disease marker protein is SHC1. In embodiments, the fibrotic pulmonary disease marker protein is SRCN1.
  • the expression level of AMPK a2b2g1, CAMK2A, CAMK2B, CAMK2D, COMMD7, FER, FYN, Integrin a1b1, LYNB, METAP1, MMP-3, PDPK1, phosphoglycerate kinase 1, SHC1, or SRCN1 is determined.
  • the expression level of AMPK a2b2g1, CAMK2A, CAMK2B, CAMK2D, COMMD7, FER, FYN, Integrin a1b1, LYNB, METAP1, MMP-3, PDPK1, phosphoglycerate kinase 1, SHC1, and SRCN1 is determined.
  • the expression level of AMPK a2b2g1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CAMK2A and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CAMK2B and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CAMK2D and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of COMMD7 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of FER and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of FYN and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Integrin a1b1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of LYNB and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of METAP1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of MMP-3 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PDPK1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of phosphoglycerate kinase 1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SHC1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SRCN1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • kits and compositions may include determining (detecting) the expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B.
  • the fibrotic pulmonary disease marker protein is TIMP-1, MMP-7, PTN, Activin A, HGF, Midkine, VEGF121, PDE3A, SBDS, Dkk-4, sICAM-5, SREC-I, ERK-1, DKK1, a2-Macroglobulin, NAGK, UFC1, or SGTA.
  • the fibrotic pulmonary disease marker protein is TIMP-1, MMP-7, PTN, Activin A, HGF, Midkine, VEGF121, PDE3A, SBDS, Dkk-4, sICAM-5, SREC-I, ERK-1, DKK1, a2-Macroglobulin, NAGK, UFC1, and SGTA.
  • the fibrotic pulmonary disease marker protein is TIMP-1.
  • the fibrotic pulmonary disease marker protein is MMP-7.
  • the fibrotic pulmonary disease marker protein is PTN.
  • the fibrotic pulmonary disease marker protein is Activin A.
  • the fibrotic pulmonary disease marker protein is HGF.
  • the fibrotic pulmonary disease marker protein is Midkine. In embodiments, the fibrotic pulmonary disease marker protein is VEGF121. In embodiments, the fibrotic pulmonary disease marker protein is PDE3A. In embodiments, the fibrotic pulmonary disease marker protein is SBDS. In embodiments, the fibrotic pulmonary disease marker protein is Dkk-4. In embodiments, the fibrotic pulmonary disease marker protein is sICAM-5. In embodiments, the fibrotic pulmonary disease marker protein is SREC-I. In embodiments, the fibrotic pulmonary disease marker protein is ERK-1. In embodiments, the fibrotic pulmonary disease marker protein is DKK1. In embodiments, the fibrotic pulmonary disease marker protein is a2-Macroglobulin.
  • the fibrotic pulmonary disease marker protein is NAGK. In embodiments, the fibrotic pulmonary disease marker protein is UFC1. In embodiments, the fibrotic pulmonary disease marker protein is SGTA. In embodiments, the expression level of TIMP-1, MMP-7, PTN, Activin A, HGF, Midkine, VEGF121, PDE3A, SBDS, Dkk-4, sICAM-5, SREC-I, ERK-1, DKK1, a2-Macroglobulin, NAGK, UFC1, or SGTA is determined.
  • the expression level of TIMP-1, MMP-7, PTN, Activin A, HGF, Midkine, VEGF121, PDE3A, SBDS, Dkk-4, sICAM-5, SREC-I, ERK-1, DKK1, a2-Macroglobulin, NAGK, UFC1, and SGTA is determined.
  • the expression level of CCL18 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of YKL40 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of TIMP-1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of MMP-7 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PTN and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Activin A and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of HGF and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Midkine and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of VEGF121 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PDE3A and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SBDS and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Dkk-4 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of sICAM-5 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SREC-I and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of ERK-1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of DKK1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of a2-Macroglobulin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of NAGK and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of UFC1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SGTA and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the fibrotic pulmonary disease marker protein is PGRP-S, sFRP-3, P-Cadherin, SSRP1, a2-HS-Glycoprotein, Persephin, ABL2, SCF sR, EMR2, MSP, Marapsin, NXPH1, ZAP70, CHL1, Rb, CAD15, CK-MB, IL-1 sR9, Lymphotoxin a2/b1, PH, Survivin, IL-6 sRa, CLC7A, 17-beta-HSD 1, or NCAM-120.
  • the fibrotic pulmonary disease marker protein is PGRP-S, sFRP-3, P-Cadherin, SSRP1, a2-HS-Glycoprotein, Persephin, ABL2, SCF sR, EMR2, MSP, Marapsin, NXPH1, ZAP70, CHL1, Rb, CAD15, CK-MB, IL-1 sR9, Lymphotoxin a2/b1, PH, Survivin, IL-6 sRa, CLC7A, 17-beta-HSD 1, and NCAM-120.
  • the fibrotic pulmonary disease marker protein is PGRP-S.
  • the fibrotic pulmonary disease marker protein is sFRP-3.
  • the fibrotic pulmonary disease marker protein is P-Cadherin. In embodiments, the fibrotic pulmonary disease marker protein is SSRP1. In embodiments, the fibrotic pulmonary disease marker protein is a2-HS-Glycoprotein. In embodiments, the fibrotic pulmonary disease marker protein is Persephin. In embodiments, the fibrotic pulmonary disease marker protein is ABL2. In embodiments, the fibrotic pulmonary disease marker protein is SCF sR. In embodiments, the fibrotic pulmonary disease marker protein is EMR2. In embodiments, the fibrotic pulmonary disease marker protein is MSP. In embodiments, the fibrotic pulmonary disease marker protein is Marapsin. In embodiments, the fibrotic pulmonary disease marker protein is NXPH.
  • the fibrotic pulmonary disease marker protein is ZAP70. In embodiments, the fibrotic pulmonary disease marker protein is CHL1. In embodiments, the fibrotic pulmonary disease marker protein is Rb. In embodiments, the fibrotic pulmonary disease marker protein is CAD15. In embodiments, the fibrotic pulmonary disease marker protein is CK-MB. In embodiments, the fibrotic pulmonary disease marker protein is IL-1 sR9. In embodiments, the fibrotic pulmonary disease marker protein is Lymphotoxin a2/b1. In embodiments, the fibrotic pulmonary disease marker protein is PH. In embodiments, the fibrotic pulmonary disease marker protein is Survivin. In embodiments, the fibrotic pulmonary disease marker protein is IL-6 sRa.
  • the fibrotic pulmonary disease marker protein is CLC7A. In embodiments, the fibrotic pulmonary disease marker protein is 17-beta-HSD 1. In embodiments, the fibrotic pulmonary disease marker protein is NCAM-120. In embodiments, the expression level of PGRP-S, sFRP-3, P-Cadherin, SSRP1, a2-HS-Glycoprotein, Persephin, ABL2, SCF sR, EMR2, MSP, Marapsin, NXPH1, ZAP70, CHL1, Rb, CAD15, CK-MB, IL-1 sR9, Lymphotoxin a2/b1, PH, Survivin, IL-6 sRa, CLC7A, 17-beta-HSD 1, or NCAM-120 is determined.
  • the expression level of PGRP-S, sFRP-3, P-Cadherin, SSRP1, a2-HS-Glycoprotein, Persephin, ABL2, SCF sR, EMR2, MSP, Marapsin, NXPH1, ZAP70, CHL1, Rb, CAD15, CK-MB, IL-1 sR9, Lymphotoxin a2/b1, PH, Survivin, sRa, CLC7A, 17-beta-HSD 1, and NCAM-120 is determined.
  • the expression level of PGRP-S and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected) (detected).
  • the expression level of sFRP-3 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of P-Cadherin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SSRP1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of a2-HS-Glycoprotein and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Persephin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of ABL2 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of SCF sR and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of EMR2 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of MSP and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Marapsin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of NXPH1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of ZAP70 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CHL1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Rb and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CAD15 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CK-MB and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of IL-1 sR9 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Lymphotoxin a2/b1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of PH and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of Survivin and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of IL-6 sRa and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of CLC7A and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of 17-beta-HSD 1 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of NCAM-120 and one or more fibrotic pulmonary disease marker proteins as provided herein is determined (detected).
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A and/or Table 4B may be determined (detected) in combination with the expression level of known markers associated with fibrotic pulmonary diseases.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of MMP7, PARC/CCL18, YKL-40(Chitinase-Like-3), MMP3, SP-D, KL-6/Muc1, or Osteopontin (OPN).
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of MMP7, PARC/CCL18, YKL-40(Chitinase-Like-3), MMP3, SP-D, KL-6/Muc1, and Osteopontin (OPN).
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of MMP1, SP-A, S100a12 (enrage), Periostin, ICAM1, VCAM, IL8, VEGF, CD28, Hsp47, IL6, LDH, PAI-1, Protein C, Thrombomodulin, vonWillebrand Factor (vWF), MMP8, IL2Ralpha, IL2Rgamma, TGFB1, TGFb2, TGFb3, or TNFalpha.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of MMP1, SP-A, S100a12 (enrage), Periostin, ICAM1, VCAM, IL8, VEGF, CD28, Hsp47, IL6, LDH, PAI-1, Protein C, Thrombomodulin, vonWillebrand Factor (vWF), MMP8, IL2Ralpha, IL2Rgamma, TGFB1, TGFb2, TGFb3, and TNFalpha.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of BNP, albumin, COMP, CCL11, CCL13, CCL17, Serum amyloid A, or CXCL13.
  • the expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A or Table 4B is determined in combination with the expression level of BNP, albumin, COMP, CCL11, CCL13, CCL17, Serum amyloid A, and CXCL13.
  • Plasma samples were obtained from IPF patients. Plasma samples for demographically matched healthy control subjects with a summary of health conditions and information regarding medication use were obtained from a separate collection protocol. All samples were obtained under appropriate written Informed Consent. Histories were reviewed to provide the best possible match of IPF and control groups. This excluded significant pulmonary disease from the healthy control group and recent use of prednisolone or other drugs (other than proton pump inhibitors) used off label in the treatment of IPF from the IPF cohort.
  • IPF patient samples were selected to include all patients that died. In addition, IPF patient samples were selected to include patients that experienced a broad range of subsequent FVC change. The ratio of male and female IPF patients (2.5:1) is similar to that in the IPF population. Control samples were selected for a balanced design across groups. Normal Healthy control subjects were selected to be demographically consistent with the IPF patient samples for consistency with the clinical trial population (age/gender). Normal Healthy control samples were collected into comparable collection vials (i.e. with matched preservatives). Both IPF and control samples were collected at multiple sites.
  • FIG. 2 shows a plot of the highest ranked processes associated with differentially expressed proteins in IPF (Y axis) compared to the processes associated with the proteins on the panel as a whole (X axis). The processes highlighted in the red box (lower right section) are enriched in IPF.
  • Table II lists the associated processes that show a shift of at least 10 positions between IPF and the panel as a whole (with processes associated with the greatest change in rank at the top). Among these processes are those involved in TGF-B signaling, cell adhesion, and epithelial mesenchymal transition (EMT). These processes are known to be associated with IPF and fibrotic conditions and suggest that the plasma proteomic signature obtained is consistent with disease state.
  • EMT epithelial mesenchymal transition
  • IPF plasma protein profile shows activation of pathways involved in TGF- ⁇ signaling, cell adhesion, and EMT.
  • Rank Rank Increase in IPF (X-Y) (Y-axis) Process Networks 66 17 Cardiac development BMP TGF beta signaling 65 22 Cell adhesion Synaptic contact 50 30 Cytoskeleton Maropinocytosis and its regulation 47 13 Apoptosis Anti-Apoptosis mediated by external signals by Estrogen 34 35 Reproduction Spermatogenesis, motility and copulation 32 44 Reproduction GnRH signaling pathway 28 49 Reproduction Gonadotropin regulation 25 16 Reproduction Male sex differentiation 25 38 Signal Transduction TGF-beta, GDF and Activin signaling 23 7 Cell cycle G1-S Growth factor regulation 22 14 Development Neurogenesis Axonal guidance 19 5 Development EMT Regulation of epithelial-to-mesenchymal transition 19 42 Inflammation MIF signaling 17 12 Cell adhesion Attractive and repulsive receptors 17 40 Development Synaptogenesis 17 41 Cell
  • Protein concentrations and patient outcomes were analyzed using R.
  • disease progression was defined as death or a ⁇ 10% absolute decrease in percent predicted FVC or a ⁇ 15% absolute decrease in percent predicted DLCO (corrected for Hb) at any time compared to baseline, documented by at 2 consecutive assessments performed at least 6 weeks apart. Patients were followed from Baseline to last known survival date or completion of study, whichever is shortest. Patients undergoing lung transplant were censored at the time of transplant.
  • Unsupervised Hierarchical Clustering was performed based on a subset of 150 differentially expressed proteins that met more stringent inclusion criteria (FDR ⁇ 0.001 and FC>1.25). The Partek Genomics Suite was used for this analysis (Partek, St. Louis, Mo.). In this analysis, the majority IPF patients cluster together ( FIG. 3 branches 5-7). Most of the remaining patients form a secondary cluster has increased similarity to healthy controls ( FIG. 3 ; branch 1). One cluster of upregulated proteins and one cluster of downregulated proteins are consistent across the majority of IPF patients. The consistently upregulated proteins ( FIG. 4 ) includes the previously reported IPF plasma protein markers MMP-7 and CCL-18. Seven of the 17 protein in this cluster are differentially upregulated at the mRNA level in IPF lung tissue (InterMune analysis of data in the GEO database).
  • differentially expressed proteins correspond to mRNAs previously shown to be differentially expressed in IPF lung tissue
  • Table IIIA and IIIB Bivariate analysis of the association between mortality and plasma protein levels (i.e. MMP-7, CCL-18, YKL-40, Activin A and A2M) by Cox proportional hazards regression model. Protein levels were quantitated by ELISA in two independent patient cohorts (i.e. Cohort 1 in Table IIIA and Cohort 2 in Table IIIB).
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; (ii) determining an expression level of a fibrotic pulmonary disease marker protein or fragment thereof set forth in Table 1A or Table 1B in said biological sample.
  • determining comprises: (a) contacting a fibrotic pulmonary disease marker protein with a marker protein binding agent in said biological sample, thereby forming a disease marker protein-binding agent complex; and (b) detecting said disease marker protein-binding agent complex.
  • detecting comprises contacting said disease marker protein-binding agent complex with a capturing agent, thereby forming a captured disease marker protein-binding agent complex.
  • said detecting further comprises: (1) contacting said captured disease marker protein-binding agent complex with a tagging moiety; thereby forming a tagged disease marker protein-binding agent complex; and (2) separating said tagged disease marker protein-binding agent complex from said biological sample.
  • said detecting further comprises after said separating of step (2) separating said capturing binding agent from said tagged disease marker protein-binding agent complex, thereby forming a cleaved disease marker protein-binding agent complex.
  • said detecting further comprises: (3) separating said marker protein binding agent from said cleaved disease marker protein-binding agent complex; thereby forming a released marker protein binding agent; and (4) determining an amount of released marker protein binding agent.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • said blood-derived biological sample is whole blood, serum or plasma.
  • said agonist is a peptide, small molecule, nucleic acid, antibody or aptamer.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 1A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • the method of embodiment 31, further comprising selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • said biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a fibrotic pulmonary disease patient; (ii) determining whether said expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 1A or Table 1B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 1A or Table 1B to said first expression level of a protein set forth in Table 1A or Table 1B, wherein when said second expression level of a protein set forth in Table 1A is greater than said first level of a protein set forth in Table 1A, or wherein when said second expression level of a protein set forth in Table 1B is smaller than said first level of a protein set forth in Table 1B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • invention 52 further comprising administering a fibrotic pulmonary disease treatment after said determining in step (i).
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether said expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in said patient; and (iii) based at least in part on said expression level in step (ii), determining said fibrotic pulmonary disease activity in said patient.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 1A or Table 1B to said first expression level of a protein set forth in Table 1A or Table 1B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in a patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in said patient at a second time point; and (iii) comparing said second expression level of a protein set forth in Table 1A or Table 1B to said first expression level of a protein set forth in Table 1A or Table 1B, thereby determining said change in fibrotic pulmonary disease activity in the patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether said expression level is modulated relative to a standard control, thereby determining a change in fibrotic pulmonary disease activity in said patient; and (iii) based at least in part on said expression level in step (ii), determining said change in fibrotic pulmonary disease activity in said patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 1A or Table 1B to the first expression level of a protein set forth in Table 1A or Table 1B, thereby determining the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby monitoring the effect of treatment for a fibrotic pulmonary disease in the patient; and (iii) based at least in part on the expression level in step (ii), monitoring the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 1A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 1B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 1A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 1B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 1A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 1B, thereby treating said subject.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in said biological sample.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 3A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 3A or 3B in a fibrotic pulmonary disease patient; (ii) determining whether said expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 3A or 3B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, wherein when said second expression level of a protein set forth in Table 3A or Table 3B is greater than said first level of a protein set forth in Table 3A or Table 3B, or wherein when said second expression level of a protein set forth in Table 3A or Table 3B is smaller than said first level of a protein set forth in Table 3A or Table 3B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether said expression level is modulated relative to a standard control, thereby determining a fibrotic pulmonary disease activity in said patient; and (iii) based at least in part on said expression level in step (ii), determining said fibrotic pulmonary disease activity in said patient.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in a patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; and (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, thereby determining said change in fibrotic pulmonary disease activity in the patient.
  • a method of determining a change in fibrotic pulmonary disease activity in a patient comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether said expression level is modulated relative to a standard control, thereby determining a change in fibrotic pulmonary disease activity in said patient; and (iii) based at least in part on said expression level in step (ii), determining said change in fibrotic pulmonary disease activity in said patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in the patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in the patient at a second time point; and (iii) comparing the second expression level of a protein set forth in Table 3A or Table 3B to the first expression level of a protein set forth in Table 3A or Table 3B, thereby determining the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of monitoring the effect of treatment for a fibrotic pulmonary disease in a patient undergoing fibrotic pulmonary disease therapy or a patient that has received fibrotic pulmonary disease therapy comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether the expression level is modulated relative to a standard control, thereby monitoring the effect of treatment for a fibrotic pulmonary disease in the patient; and (iii) based at least in part on the expression level in step (ii), monitoring the effect of treatment for a fibrotic pulmonary disease in the patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 3A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 3B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 3A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 3B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 3A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 3B, thereby treating said subject.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a kit comprising: (a) a marker protein binding agent capable of binding to a substance within a biological sample from a human subject having or at risk of developing a fibrotic pulmonary disease; wherein said substance is a fibrotic pulmonary disease marker protein or fragment thereof set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B; (b) a detecting reagent or a detecting apparatus capable of indicating binding of said marker protein binding agent to said substance.
  • the kit of embodiment 94 further comprising: c) a sample collection device for collecting a sample from a subject.
  • kit of embodiment 94 or 95 wherein said subject has a fibrotic pulmonary disease.
  • a complex in vitro comprising a marker protein binding agent bound to a fibrotic pulmonary disease marker protein or fragment thereof set forth in Table 1A, 1B, 2A, 2B, 3A, 3B, 4A, or 4B, wherein said fibrotic pulmonary disease marker protein is extracted from a human subject having or at risk of developing a fibrotic pulmonary disease.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B in said biological sample.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 1A or Table 1B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 1A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 1B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • the method of embodiment 121 further comprising selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • the method embodiment 127 wherein said biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 1A or Table 1B to said first expression level of a protein set forth in Table 1A or Table 1B, wherein when said second expression level of a protein set forth in Table 1A is greater than said first level of a protein set forth in Table 1A, or wherein when said second expression level of a protein set forth in Table 1B is smaller than said first level of a protein set forth in Table 1B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • the method of embodiment 140 further comprising administering a fibrotic pulmonary disease treatment after said determining in step (i).
  • invention 140 further comprising determining a rate of progression of said fibrotic pulmonary disease in said patient based on said comparing.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 1A or Table 1B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 1A or Table 1B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 1A or Table 1B to said first expression level of a protein set forth in Table 1A or Table 1B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 1A or Table 1B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 1A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 1B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 1A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 1B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 1A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 1B, thereby treating said subject.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 1A or 1B in a fibrotic pulmonary disease patient; (ii) determining whether said expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 1A or 1B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in said biological sample.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 3A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, wherein when said second expression level of a protein set forth in Table 3A is greater than said first level of a protein set forth in Table 3A, or wherein when said second expression level of a protein set forth in Table 1B is smaller than said first level of a protein set forth in Table 1B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 3A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 3B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 3A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 3B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 3A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 3B, thereby treating said subject.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 3A or 3B in a fibrotic pulmonary disease patient; (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 3A or 3B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease; and (iii) based at least in part on the expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 2A or Table 2B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 2A or Table 2B in said biological sample.
  • invention 169 further comprising selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • fibrotic pulmonary disease marker protein is a progressive fibrotic pulmonary disease marker protein.
  • invention 178 further comprising administering to said subject an effective amount of a modulator of said fibrotic pulmonary disease marker protein set forth in Table 2A.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 2A or Table 2B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 2A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 2B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • invention 191 further comprising selecting a subject that has or is at risk for developing a fibrotic pulmonary disease.
  • fibrotic pulmonary disease is idiopathic pulmonary fibrosis or familial interstitial pneumonia.
  • the method embodiment 197 wherein said biological sample is urine, saliva, a pulmonary tissue, bronchoalveolar lavage sample, or exhaled breath condensate.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 2A or Table 2B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 2A or Table 2B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 2A or Table 2B to said first expression level of a protein set forth in Table 2A or Table 2B, wherein when said second expression level of a protein set forth in Table 2A is greater than said first level of a protein set forth in Table 2A, or wherein when said second expression level of a protein set forth in Table 2B is smaller than said first level of a protein set forth in Table 2B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • invention 210 further comprising administering a fibrotic pulmonary disease treatment after said determining in step (i).
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 2A or Table 2B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 2A or Table 2B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 2A or Table 2B to said first expression level of a protein set forth in Table 2A or Table 2B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 2A or Table 2B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 2A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 2B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 2A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 2B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 2A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 2B, thereby treating said subject.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 2A or 2B in a fibrotic pulmonary disease patient; (ii) determining whether said expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 2A or 2B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of said fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in a subject that has or is at risk for developing a fibrotic pulmonary disease comprising: (i) obtaining a biological sample from said subject; and (ii) determining an expression level of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B in said biological sample.
  • a method of determining whether a subject has or is at risk of developing a fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker proteins set forth in Table 3A or Table 3B in a subject; (ii) determining whether said expression level is increased or decreased relative to a standard control, wherein an elevated expression level of a fibrotic pulmonary disease marker protein in Table 3A or a decreased expression level of a fibrotic pulmonary disease marker protein in Table 3B relative to said standard control indicates that said subject has or is at risk of developing a fibrotic pulmonary disease; and (iii) based at least in part on said expression level in step (ii), determining whether said subject has or is at risk for developing a fibrotic pulmonary disease.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, wherein when said second expression level of a protein set forth in Table 3A is greater than said first level of a protein set forth in Table 3A, or wherein when said second expression level of a protein set forth in Table 3B is smaller than said first level of a protein set forth in Table 3B, the patient is at risk for progression of the fibrotic pulmonary disease.
  • a method of determining a fibrotic pulmonary disease activity in a patient comprising: (i) determining a first expression level of a protein set forth in Table 3A or Table 3B in said patient at a first time point; (ii) determining a second expression level of a protein set forth in Table 3A or Table 3B in said patient at a second time point; (iii) comparing said second expression level of a protein set forth in Table 3A or Table 3B to said first expression level of a protein set forth in Table 3A or Table 3B, thereby determining said fibrotic pulmonary disease activity in said patient.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising administering to said subject an effective amount of an modulator of a fibrotic pulmonary disease marker protein set forth in Table 3A or Table 3B, thereby treating a fibrotic pulmonary disease in said subject.
  • a method of treating a fibrotic pulmonary disease in a subject in need thereof comprising: (i) determining whether a subject expresses an elevated level of a fibrotic pulmonary disease marker protein as set forth in Table 3A or a decreased level of a fibrotic pulmonary disease marker protein as set forth in Table 3B relative to a standard control; and (ii) when an elevated expression level of said fibrotic pulmonary disease marker protein of Table 3A or a decreased expression level of said fibrotic pulmonary disease marker protein of Table 3B is found relative to said standard control, administering to said subject a fibrotic pulmonary disease treatment, an antagonist of a fibrotic pulmonary disease marker protein set forth in Table 3A or an agonist of a fibrotic pulmonary disease marker protein set forth in Table 3B, thereby treating said subject.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.
  • a method of determining whether a fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease comprising: (i) detecting an expression level of one or more fibrotic pulmonary disease marker protein set forth in Table 3A or 3B in a fibrotic pulmonary disease patient; (ii) determining whether the expression level is modulated relative to a standard control, wherein a modulated expression level of a fibrotic pulmonary disease marker protein in Table 3A or 3B relative to said standard control indicates that said fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease; and (iii) based at least in part on the expression level in step (ii), determining whether said fibrotic pulmonary disease patient is at risk for progression of the fibrotic pulmonary disease.
  • determining whether the expression level is modulated relative to a standard control comprises determining whether the expression level is elevated or suppressed relative to other fibrotic pulmonary disease patients.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Pathology (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Cell Biology (AREA)
  • General Physics & Mathematics (AREA)
  • Food Science & Technology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biophysics (AREA)
  • General Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
US14/213,970 2013-03-15 2014-03-14 Proteomic IPF markers Active - Reinstated US9726677B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US14/213,970 US9726677B2 (en) 2013-03-15 2014-03-14 Proteomic IPF markers

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201361801290P 2013-03-15 2013-03-15
US201361801476P 2013-03-15 2013-03-15
US201361874947P 2013-09-06 2013-09-06
US14/213,970 US9726677B2 (en) 2013-03-15 2014-03-14 Proteomic IPF markers

Publications (2)

Publication Number Publication Date
US20140286929A1 US20140286929A1 (en) 2014-09-25
US9726677B2 true US9726677B2 (en) 2017-08-08

Family

ID=51537804

Family Applications (1)

Application Number Title Priority Date Filing Date
US14/213,970 Active - Reinstated US9726677B2 (en) 2013-03-15 2014-03-14 Proteomic IPF markers

Country Status (11)

Country Link
US (1) US9726677B2 (ru)
EP (1) EP2972392A4 (ru)
JP (1) JP2016519763A (ru)
KR (1) KR20150130408A (ru)
CN (1) CN105122068A (ru)
BR (1) BR112015023699A2 (ru)
CA (1) CA2901384A1 (ru)
HK (1) HK1219533A1 (ru)
MX (1) MX2015012778A (ru)
RU (1) RU2015144149A (ru)
WO (1) WO2014144821A1 (ru)

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11976329B2 (en) 2013-03-15 2024-05-07 Veracyte, Inc. Methods and systems for detecting usual interstitial pneumonia
MX2015012778A (es) 2013-03-15 2016-01-20 Intermune Inc Marcadores proteomicos de fibrosis pulmonar idiopatica (fpi).
CN107206043A (zh) * 2014-11-05 2017-09-26 维拉赛特股份有限公司 使用机器学习和高维转录数据在经支气管活检上诊断特发性肺纤维化的系统和方法
US10975167B2 (en) 2017-04-14 2021-04-13 Arizona Board Of Regents On Behalf Of The University Of Arizona Method to reduce pulmonary arterial hypertension by administering inhibitors of nicotinamide phosphoribotransferase
WO2018191751A1 (en) * 2017-04-14 2018-10-18 Arizona Board Of Regents On Behalf Of The University Of Arizonia Compositions and methods for treating pulmonary fibrosis
CN107677835B (zh) * 2017-09-26 2019-08-09 上海市肺科医院 一种ae-ipf的蛋白标记物及其应用
BR112021002728A2 (pt) * 2018-08-17 2021-08-10 F. Hoffmann-La Roche Ag métodos de avaliação da fibrilação atrial, de auxílio à avaliação da fibrilação atrial, de diagnóstico de insuficiência cardíaca e de predição do risco de hospitalização, método implementado por computador para a avaliação da fibrilação atrial, kit e usos in vitro
EP3875958A4 (en) * 2018-10-29 2022-10-05 National University Corporation Tokyo Medical and Dental University METHOD OF GATHERING INFORMATION ABOUT THE RISK OF REDUCED RESPIRATORY FUNCTIONING IN PATIENTS WITH INTERSTITIAL PNEUMONIA AND USE THEREOF
JP7300642B2 (ja) * 2019-06-14 2023-06-30 国立大学法人浜松医科大学 特発性肺線維症の予後予測方法
JPWO2021024856A1 (ru) * 2019-08-02 2021-02-11
WO2021181368A1 (en) * 2020-03-13 2021-09-16 Puretech Lyt 100, Inc. Methods of treating respiratory disease with deupirfenidone
US20230146286A1 (en) * 2020-04-17 2023-05-11 Japan As Represented By Director General Of National Institute Of Health Sciences Protein diagnostic biomarker for severe drug eruption
CN113607955A (zh) * 2020-09-16 2021-11-05 广州中医药大学顺德医院(佛山市顺德区中医院) 新型冠状病毒肺炎分期与疗效评估细胞因子标志物及其应用
CN113533750A (zh) * 2020-10-22 2021-10-22 广州中医药大学顺德医院(佛山市顺德区中医院) 一种区分新型冠状病毒肺炎患者与健康者的系统
WO2023038416A1 (ko) * 2021-09-07 2023-03-16 주식회사 에프엔씨티바이오텍 폐 섬유증의 바이오마커 및 치료 표적으로서 csf3r
WO2023081299A1 (en) * 2021-11-05 2023-05-11 Spiritus Therapeutics, Inc. A purified enriched population exosomes derived from individuals with a chronic progressive lung disease for noninvasive detection, staging, and medical monitoring of disease progression
KR20240026005A (ko) * 2022-08-19 2024-02-27 울산대학교 산학협력단 특발성 폐섬유증 환자의 진단 및 경과예측용 호기 바이오마커
WO2024068386A1 (en) * 2022-09-28 2024-04-04 Boehringer Ingelheim International Gmbh Use of biomarkers in the treatment of fibrotic conditions with a pde4b-inhibitor
CN117025745B (zh) * 2022-11-18 2024-02-23 中国医学科学院北京协和医院 分子标志物在诊断干燥综合征中的应用

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US5582981A (en) 1991-08-14 1996-12-10 Gilead Sciences, Inc. Method for identifying an oligonucleotide aptamer specific for a target
US5595877A (en) 1990-06-11 1997-01-21 Nexstar Pharmaceuticals, Inc. Methods of producing nucleic acid ligands
US5637459A (en) 1990-06-11 1997-06-10 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: chimeric selex
US6019988A (en) 1996-11-18 2000-02-01 Bristol-Myers Squibb Company Methods and compositions for enhancing skin permeation of drugs using permeation enhancers, when drugs and/or permeation enhancers are unstable in combination during long-term storage
WO2004009776A2 (en) 2002-07-19 2004-01-29 Abbott Biotechnology Ltd. TREATMENT OF TNFα RELATED DISORDERS
US20040234519A1 (en) * 2003-03-26 2004-11-25 Tso J. Yun Anti-pleiotrophin antibodies and methods of use thereof
WO2010028274A1 (en) 2008-09-05 2010-03-11 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Marker panels for idiopathic pulmonary fibrosis diagnosis and evaluation
US20100227335A1 (en) * 2009-03-05 2010-09-09 Becton, Dickinson And Company Matrix metalloproteinase-7 (mmp-7) monoclonal antibodies and methods for their use in the detection of ovarian cancer
US20110076280A1 (en) * 2007-08-24 2011-03-31 Oncotherapy Science, Inc. Dkk1 oncogene as therapeutic target for cancer and a diagnosing marker
WO2011054893A2 (en) 2009-11-05 2011-05-12 Novartis Ag Biomarkers predictive of progression of fibrosis
US7981621B2 (en) * 2005-08-26 2011-07-19 Cezanne S.A.S. In vitro method for diagnosing and monitoring renal cell carcinoma (RCC) using MMP-7 as humoral biomarker for RCC
US20110250589A1 (en) 2010-01-21 2011-10-13 The Regents Of The University Of Michigan Biomarkers for lung disease monitoring
US20110280865A1 (en) 2009-01-16 2011-11-17 The Ohio State University Ets-2 Biomarkers for Fibrotic Diseases and Uses Thereof
US20130078252A1 (en) * 2011-09-19 2013-03-28 Genentech, Inc. Combination treatments comprising c-met antagonists and b-raf antagonists
WO2014144821A1 (en) 2013-03-15 2014-09-18 Intermune, Inc. Proteomic ipf markers

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2002307494A1 (en) * 2001-04-24 2002-11-05 Bayer Corporation Human timp-1 antibodies
AUPR638101A0 (en) * 2001-07-13 2001-08-09 Bioa Pty Limited Composition and method for treatment of disease
JP2003238592A (ja) * 2001-12-13 2003-08-27 Japan Tobacco Inc 組織及び血管の再生のための医薬及びその方法
US20060211752A1 (en) * 2004-03-16 2006-09-21 Kohn Leonard D Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression
EP1626279B1 (en) * 2004-08-12 2008-04-16 Roche Diagnostics GmbH Method for diagnosing liver fibrosis
CN101160528A (zh) * 2005-02-14 2008-04-09 惠氏公司 Il17-f在诊断和治疗气道炎症中的用途
US20110129845A1 (en) * 2007-01-29 2011-06-02 Crc For Asthma And Airways Ltd. Method of diagnosis
WO2010047938A2 (en) * 2008-10-21 2010-04-29 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Mmp activation peptide detection in biological samples
MX2011009810A (es) * 2009-03-27 2011-09-30 Zymogenetics Inc Composiciones y metodos para usar proteinas de union multiespecificas que comprenden una combinacion anticuerporeceptor.
KR20120054077A (ko) * 2009-08-21 2012-05-29 길리아드 바이오로직스, 인크. 폐 섬유증 장애의 치료를 위한 방법 및 조성물

Patent Citations (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5235033A (en) 1985-03-15 1993-08-10 Anti-Gene Development Group Alpha-morpholino ribonucleoside derivatives and polymers thereof
US5595877A (en) 1990-06-11 1997-01-21 Nexstar Pharmaceuticals, Inc. Methods of producing nucleic acid ligands
US5637459A (en) 1990-06-11 1997-06-10 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: chimeric selex
US5582981A (en) 1991-08-14 1996-12-10 Gilead Sciences, Inc. Method for identifying an oligonucleotide aptamer specific for a target
US6019988A (en) 1996-11-18 2000-02-01 Bristol-Myers Squibb Company Methods and compositions for enhancing skin permeation of drugs using permeation enhancers, when drugs and/or permeation enhancers are unstable in combination during long-term storage
WO2004009776A2 (en) 2002-07-19 2004-01-29 Abbott Biotechnology Ltd. TREATMENT OF TNFα RELATED DISORDERS
US20040234519A1 (en) * 2003-03-26 2004-11-25 Tso J. Yun Anti-pleiotrophin antibodies and methods of use thereof
US7981621B2 (en) * 2005-08-26 2011-07-19 Cezanne S.A.S. In vitro method for diagnosing and monitoring renal cell carcinoma (RCC) using MMP-7 as humoral biomarker for RCC
US20110076280A1 (en) * 2007-08-24 2011-03-31 Oncotherapy Science, Inc. Dkk1 oncogene as therapeutic target for cancer and a diagnosing marker
WO2010028274A1 (en) 2008-09-05 2010-03-11 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Marker panels for idiopathic pulmonary fibrosis diagnosis and evaluation
US20120035067A1 (en) 2008-09-05 2012-02-09 Naftali Kaminski Marker Panels For Idiopathic Pulmonary Fibrosis Diagnosis And Evaluation
US20110280865A1 (en) 2009-01-16 2011-11-17 The Ohio State University Ets-2 Biomarkers for Fibrotic Diseases and Uses Thereof
US20100227335A1 (en) * 2009-03-05 2010-09-09 Becton, Dickinson And Company Matrix metalloproteinase-7 (mmp-7) monoclonal antibodies and methods for their use in the detection of ovarian cancer
WO2011054893A2 (en) 2009-11-05 2011-05-12 Novartis Ag Biomarkers predictive of progression of fibrosis
US20120282276A1 (en) 2009-11-05 2012-11-08 The Regents Of The University Of Michigan Biomarkers predictive of progression of fibrosis
US20110250589A1 (en) 2010-01-21 2011-10-13 The Regents Of The University Of Michigan Biomarkers for lung disease monitoring
US20130078252A1 (en) * 2011-09-19 2013-03-28 Genentech, Inc. Combination treatments comprising c-met antagonists and b-raf antagonists
WO2014144821A1 (en) 2013-03-15 2014-09-18 Intermune, Inc. Proteomic ipf markers

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
American Thoracic Society et al. (Jan. 15, 2002). "American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, Jun. 2001 and by the ERS Executive Committee, Jun. 2001," Am J Respir Crit Care Med 165(2):277-304.
Brody, E.N. et al. (Nov. 2010). "High-content affinity-based proteomics: unlocking protein biomarker discovery," Expert Rev Mol Diagn 10(8):1013-1022.
Coche, E. et al. (Feb. 2001). "Non-specific interstitial pneumonia showing a "crazy paving" pattern on high resolution CT," Br J Radiol 74(878):189-191.
Desai, B. et al. (Jan. 2009). "Differential Cellular and Molecular Markers in Idiopathic Pulmonary Fibrosis," American Journal of Respiratory and Critical Care Medicine; American Thoracic Society 2009 international Conference, American Lung Association vol. 179, p. A3488, Meeting Abstracts.
Entrez entry for gene ID No. 8578 downloaded from NCBI https://www.ncbi.nlm.nih.gov/gene/?term=8578 on Mar. 30, 2017. *
Fingerlin, T.E. et al. (Jun. 2013, e-published Apr. 14, 2013). "Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis," Nature Genetics 45(6):613-620.
International Search Report mailed on Jul. 17, 2014, for PCT Application No. PCT/US2014/029392, filed Mar. 14, 2014, 4 pages.
Ishii et al. J. Biol. Chem. (2002) 277(42): 39696-39702. *
Ma, S. et al. (Jul. 1, 2011, e-published May 13, 2011). "Quantitation of desmosine and isodesmosine in urine, plasma, and sputum by LC-MS/MS as biomarkers for elastin degradation" J Chromatogr B Analyt Technol Biomed Life Sci 879(21):1893-1898.
Pavan et al. Endocrinology (2004) 145(10): 4583-4591. *
Raghu, G. et al. (Oct. 1, 2006, e-published Jun. 29, 2006). "Incidence and prevalence of idiopathic pulmonary fibrosis," Am J Respir Crit Care Med 174(7):810-816.
Rosas, I.O. et al. (Apr. 29, 2008). "MMP1 and MMP7 as potential peripheral blood biomarkers in idiopathic pulmonary fibrosis," PLoS Med 5(4):623-633.
Selman, M. et al. (2000). "TIMP-1, -2, -3 and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment?" American Journal of Physiology-Lung Cellular and Molecular Physiology Sep 279(3):L562-L574.
Tazelaar, H.D. et al. (Mar. 2011, e-published Sep. 21, 2010). "Desquamative interstitial pneumonia," Histopathology 58(4):509-516.
Thomeer, M. et al. (Jun. 28, 2010). "Clinical use of biomarkers of survival in pulmonary fibrosis," Respiratory Research 11:89.
Tzouvelekis, A. et al. (Jul. 21, 2005). "Serum biomarkers in interstitial lung diseases," Respiratory Research 6(1):78.
Wells, A.U. et al. (Oct. 2003). "Respiratory bronchiolitis-associated interstitial lung disease," Semin Respir Crit Care Med 24(5):585-594.
White, K.A. et al. (Jun. 2007). "Bronchiolitis obliterans organizing pneumonia," Crit Care Nurse 27(3):53-66.
Written Opinion mailed on Jul. 17, 2014, for PCT Application No. PCT/US2014/029392, filed Mar. 14, 2014, 7 pages.

Also Published As

Publication number Publication date
WO2014144821A1 (en) 2014-09-18
KR20150130408A (ko) 2015-11-23
CN105122068A (zh) 2015-12-02
US20140286929A1 (en) 2014-09-25
MX2015012778A (es) 2016-01-20
HK1219533A1 (zh) 2017-04-07
RU2015144149A (ru) 2017-04-21
CA2901384A1 (en) 2014-09-18
JP2016519763A (ja) 2016-07-07
EP2972392A1 (en) 2016-01-20
BR112015023699A2 (pt) 2017-07-18
EP2972392A4 (en) 2017-03-22

Similar Documents

Publication Publication Date Title
US9726677B2 (en) Proteomic IPF markers
US20170314074A1 (en) Lpa-associated protein and rna expression
Huang et al. Advances in aptamer-based biomarker discovery
US20130189243A1 (en) Biomarkers for acute ischemic stroke
US20230194536A1 (en) Markers for the diagnosis and treatment of non-alcoholic steatohepatitis (nash) and advance liver fibrosis
US20170335395A1 (en) A parkinson's disease diagnostic biomarker panel
US20210041469A1 (en) Methods and compositions for diagnosis and prognosis of sepsis
EP3504553B1 (en) System and method for analysis of biological data
US9733261B2 (en) Methods and compositions for diagnosis and prognosis of stroke or other cerebral injury
TW201537175A (zh) 預測罹患具皮膚搔癢之疾病的患者對ｉｌ－３１拮抗劑之治療的反應之方法
JP5619016B2 (ja) 重症敗血症及び敗血症性ショック中の死亡の危険性が高い患者を迅速に決定するための方法及びキット
JP2012513591A (ja) 敗血症の検出のための方法
Hassan-Zahraee et al. Baseline serum and stool microbiome biomarkers predict clinical efficacy and tissue molecular response after ritlecitinib induction therapy in ulcerative colitis
Stankovic et al. Biomarkers in Idiopathic Pulmonary Fibrosis
JP7258860B2 (ja) 抗生物質治療をモニタリングするためのマーカーとしてのｐｃｔおよびｐｒｏ－ａｄｍ
WO2014018464A1 (en) Methods and compositions for diagnosis and prognosis of sepsis
JP2021508045A (ja) 併存症を有する患者におけるプロカルシトニンに基づく抗生物質療法のガイダンス
Parker et al. Multiple serum biomarkers associate with mortality and interstitial lung disease progression in systemic sclerosis
US20240192227A1 (en) Methods of diagnosing and predicting renal decline
Wang et al. Methods and clinical biomarker discovery for targeted proteomics using Olink technology
TWI809247B (zh) 人類t細胞白血病病毒1型（htlv-1）相關疾病的診斷方法
Bonella et al. Biomarker discovery in systemic sclerosis: state of the art
Schneider et al. SOMAmer the Chemically SomaScan reagents modified platform: and aptamers and their applications in therapeutics, diagnostics, and proteomics
CN111065927B (zh) 作为危重患者的治疗监测标记物的pro-adm
Liu Biomarkers for Parkinson’s disease and Alzheimer’s disease

Legal Events

Date Code Title Description
AS Assignment

Owner name: INTERMUNE, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KOSSEN, KARL;QIN, XIAOLI;LIM, SHARLENE R.;AND OTHERS;SIGNING DATES FROM 20140523 TO 20140703;REEL/FRAME:033486/0001

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: INTERMUNE, INC., CALIFORNIA

Free format text: CHANGE OF ASSIGNEE ADDRESS;ASSIGNOR:INTERMUNE, INC.;REEL/FRAME:047969/0276

Effective date: 20181219

FEPP Fee payment procedure

Free format text: MAINTENANCE FEE REMINDER MAILED (ORIGINAL EVENT CODE: REM.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

LAPS Lapse for failure to pay maintenance fees

Free format text: PATENT EXPIRED FOR FAILURE TO PAY MAINTENANCE FEES (ORIGINAL EVENT CODE: EXP.); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362

FP Lapsed due to failure to pay maintenance fee

Effective date: 20210808

FEPP Fee payment procedure

Free format text: PETITION RELATED TO MAINTENANCE FEES FILED (ORIGINAL EVENT CODE: PMFP); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: PETITION RELATED TO MAINTENANCE FEES GRANTED (ORIGINAL EVENT CODE: PMFG); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Free format text: SURCHARGE, PETITION TO ACCEPT PYMT AFTER EXP, UNINTENTIONAL (ORIGINAL EVENT CODE: M1558); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YEAR, LARGE ENTITY (ORIGINAL EVENT CODE: M1551); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY

Year of fee payment: 4

PRDP Patent reinstated due to the acceptance of a late maintenance fee

Effective date: 20211011

STCF Information on status: patent grant

Free format text: PATENTED CASE

AS Assignment

Owner name: GENENTECH, INC., CALIFORNIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:INTERMUNE, INC.;REEL/FRAME:066998/0231

Effective date: 20240402